Introduction: Psoriasis is a chronic inflammatory skin disease with variable clinical presentation, multifactorial etiology and an immunogenetic basis. Several studies demonstrate that it results from a dysregulated interaction between skin keratinocytes, immune cells, and the environment that leads to a persistent inflammatory process modulated by cytokines and T cells. The development of new treatment options requires increased understanding of pathogenesis. However, the successful implementation of effective drugs requires well-characterized and highly available preclinical models that allow researchers to quickly and reproducibly determine their safety and efficacy. Methods: A systematic search on PubMed and Scopus databases was performed and assessed to find appropriate articles about psoriasis models applying the key words previously defined. The PRISMA guidelines were employed. Results: A total of 45 original articles were selected that met the selection criteria. Among these, there are articles on in vivo, in vitro, and ex vivo models, with the in vitro model being the majority due to its ease of use. Within animal models, the most widely used in recent years are chemically induced models using a compound known as imiquimod. However, the rest of the animal models used throughout the disease’s research were also discussed. On the other hand, in vitro models were divided into two and three dimensions. The latter were the most used due to their similarity to human skin. Lastly, the ex vivo models were discussed, although they were the least used due to their difficulty in obtaining them. Conclusions: Therefore, this review summarizes the current preclinical models (in vivo, in vitro, and ex vivo), discussing how to develop them, their advantages, limitations, and applications. There are many challenges to improve the development of the different models. However, research in these in vitro model studies could reduce the use of animals. This is favored with the use of future technologies such as 3D bioprinting or organ-on-a-chip technologies.

Psoriasis is a chronic inflammatory skin disease in which multiple genetic and environmental factors contribute to skin inflammation [1, 2]. Psoriasis vulgaris is the most frequent variant, affecting 2–3% of the world’s population, with 85–90% of psoriatic patients experiencing this type of psoriasis [3]. Therefore, psoriasis is likely the most prevalent immune-mediated skin disease in adults [4]. Moreover, it is associated with several comorbidities including obesity, arthritis, and even depression [5‒7].

Histologically, the skin of these patients is characterized by an infiltration of inflammatory cells in the dermis (dendritic cells [DCs], macrophages, and T cells) and the epidermis (neutrophils and some T cells). Furthermore, there is hyperproliferation and abnormal differentiation of keratinocytes (KTs) resulting in epidermal hyperplasia characterized by well-delimited erythematous oval plaques with adherent silvery scales, known as acanthosis. Parakeratosis, which means retention of nuclei in the stratum corneum (SC), is also found [3, 8]. All these factors, together with the inability of corneocytes to secrete extracellular lipids causing cellular adhesion, are responsible for the formation of a disturbed SC, and therefore, for an impaired permeability function [4, 9].

The reddish appearance of psoriatic lesions is attributable to blood vessels’ dilation producing leakage, and increased dermal angiogenesis. This enhanced vascularization results in increased migration of inflammatory cells into the lesions [10]. In addition, due to accelerated keratinization combined with premature cell death, psoriasis has a unique keratinization process. This leads to the disappearance of the late differentiation markers profilaggrin (pro-FLG) and loricrin and to a reduction in keratin (K) 1 and 10 in the affected epidermis. On the other hand, there is an upward regulation of involucrin, which is expressed by irreversibly differentiated KTs. All these proteins are important in the epidermal barrier function [11]. Moreover, increased expression of certain proteins that are not expressed in healthy skin, such as skin-derived anti-leukoproteinase/elafin, human β-defensin 2 or β-defensin 4 (DEFB4), K6, K16, and K17 is observed [3].

Regarding the pathogenesis of this disease, it is a fairly complex process that, although not fully understood, is discussed in more detail by Redon et al. [12]. Briefly, psoriasis is developed and maintained by the interaction of DCs and T cells with each other and with KTs, leading to both innate and adaptive immune responses [13]. Specifically, DCs and other cell types release a complex network of cytokines such as tumor necrosis factor α (TNF-α), interleukin (IL)-12, and IL-23, which play a key role in the differentiation of T cells into Th1 or Th17 phenotypes [10]. Meanwhile, Th1 cells produce interferon γ which induces KTs to produce pro-inflammatory chemokines (CXCL), including CXCL-10 and 11. These recruit more Th1-type cells into the lesion, creating a positive feedback loop. Likewise, IL-23 promotes the expansion and differentiation of Th17 cells and maintains local inflammation by activating its receptor present on Th17 cells. Upon binding, IL-23 contributes to the phosphorylation of receptor-associated Janus kinases (JAKs) and tyrosine kinases, resulting in the release of the pro-inflammatory interleukins IL-17A (key cytokine), IL-17F, and IL-22 among others [8, 14].

The binding of IL-17A to its receptor stimulates changes in both structural skin cells and immune cells. At high levels, it produces the hyperproliferation of KTs and stimulates them to produce more pro-inflammatory cytokines such as IL-36 or IL-25, which participate in their differentiation and activation. In turn, it promotes the release of CXCL-20 or IL-8 involved in the recruitment of neutrophils and macrophages at the site of inflammation. This leads to the formation of microabscesses and the attraction of more dendritic and Th17 cells, giving rise to the epidermal inflammatory response loop. IL-17F has a similar effect to IL-17A, and IL-22 potentiates the effects of these cytokines (especially IL-17A). Therefore, taken together, these activities initiate and propagate inflammation, making it chronic [15, 16]. With a lower level of regulatory T cells, the IL-23/Th17 pathway is not suppressed, leading to an immune imbalance and an inflammatory state [17]. In addition, Th17 cells increase the expression of certain chemokines, increasing the recruitment of Th1 cells and KT’s sensitivity to them [15] (Fig. 1).

Fig. 1.

Summary scheme of the pathogenesis of psoriasis. DCs release cytokines such as TNF-α, IL 12, and IL-23, which play a key role in the differentiation of T cells into Th1 or Th17 phenotypes. Th1 cells produce INF-γ which induces KTs to produce pro-inflammatory chemokines CXCL-10 and 11, recruiting more Th1-type cells into the lesion (positive feedback loop). Th17 cells produce IL-17A, IL-17F, and IL-22, among others. They induce epidermal hyperplasia and are involved in recruiting neutrophils to the site of inflammation. CXCL, chemokines; DCs, dendritic cells; IL, interleukin; INF-γ, interferon γ; JAK, Janus kinases; KTs, keratinocytes; TNF-α, tumor necrosis factor α; TYK, tyrosine kinase; VEGF, vascular endothelial growth factor. Created with biorender.com.

Fig. 1.

Summary scheme of the pathogenesis of psoriasis. DCs release cytokines such as TNF-α, IL 12, and IL-23, which play a key role in the differentiation of T cells into Th1 or Th17 phenotypes. Th1 cells produce INF-γ which induces KTs to produce pro-inflammatory chemokines CXCL-10 and 11, recruiting more Th1-type cells into the lesion (positive feedback loop). Th17 cells produce IL-17A, IL-17F, and IL-22, among others. They induce epidermal hyperplasia and are involved in recruiting neutrophils to the site of inflammation. CXCL, chemokines; DCs, dendritic cells; IL, interleukin; INF-γ, interferon γ; JAK, Janus kinases; KTs, keratinocytes; TNF-α, tumor necrosis factor α; TYK, tyrosine kinase; VEGF, vascular endothelial growth factor. Created with biorender.com.

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These pathways are the main targets of the drugs currently used for psoriasis treatment, e.g., small molecule inhibitors that act against intracellular signaling molecules. These are produced by chemical synthesis and are generally administered orally. Among these, JAK inhibitors (JAKis) are highlighted. These include tofacitinib (targets JAK1/3 and approved for psoriatic arthritis), baricitinib (targets JAK1/2 in phase II for the treatment of moderate to severe psoriasis), and deucravacitinib (selective tyrosine kinases 2 inhibitor approved by the European Union in 2023 for treating patients with moderate to severe plaque psoriasis) [18]. Nevertheless, given the heterogeneity and complexity of the disease, to date no cure has been discovered as there are patients who respond poorly to current treatments. All this together with the side effects associated with traditional systemic medical care makes it necessary to develop new therapies with an improved risk-benefit profile for all patients [1, 10, 19].

Recently, biomarkers that allow clinical follow-up of the improvement in the patient's symptomatology have been investigated. The best studied markers are those related to epidermal proliferation (Ki-67) and inflammatory infiltration (CD3, CD11c, and CD163). Furthermore, genes related to innate immunity (S100 proteins [psoriasins] and defensins), KT activation (KRT16 and PI3), and Th17 cells have been analyzed. These genes have acquired great importance for evaluating the effect of anti-inflammatory drugs. Blood biomarkers have also been identified in psoriatic patients with associated morbidity such as psoriatic arthritis (matrix metalloproteinase-3). Finally, certain microRNAs (miR-203, miR-21, and miR-125b) have been shown to be differentially regulated in involved and uninvolved skin [10]. The ultimate goal of using markers would be to select appropriate treatment for each patient, assess early relapse, or identify patients’ risk of developing disease-associated comorbidities [10, 20]. However, none of them has been considered fully predictive of disease severity, so they have not been incorporated into routine clinical practice [8].

As can be seen, progress in understanding the pathogenesis of psoriasis allows new targets for evaluating potential drugs to be discovered and more to be learned about its etiopathogenesis. To continue this progress, study models are needed that mimic all the characteristics of this disease as closely as possible. Nonetheless, a major obstacle for researchers in this field is the lack of robust and well-characterized psoriatic models. Consequently, the aim of this review was to provide an overview of the current psoriatic models (in vivo, in vitro, and ex vivo) and to analyze how they have been used in the investigation of this disease to date. The advantages, limitations, and potential application of the different models in research on the disorder have been highlighted. Importantly, researchers aiming to investigate new aspects of this disease will be able to decide which model best suits their interests, while being aware that all models have their advantages and limitations. Finally, new approaches that could be incorporated into the field in order to improve the current models are proposed.

Search Strategy

This systematic review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines [21]. On December 21, 2021, a systematic bibliographic search was performed using MeSH and free-text terms on two distinct electronic databases: “PubMed” and “Scopus.” For this, a combination of terms was used in the search algorithm: the term “PSORIASIS” [Mesh] was combined using the Boolean operator “and” with the following terms: SKIN, ARTIFICIAL” [Mesh], “SKIN SUBSTITUTE,” “SKIN MODEL,” “TISSUE ENGINEERED” or “TISSUE ENGINEERING.”

Eligibility Criteria

The inclusion criteria were: (1) in vivo, in vitro, and ex vivo studies, (2) original article, (3) written in English, (4) publications dated from 2011 to 2021. Exclusion criteria were: (1) non-research papers (books, reviews, letters to editor, protocols, clinical trials, and unpublished literature), (2) non-psoriasis articles and (3) non-artificial skin articles. Finally, a total of 45 pieces of original research about psoriatic models were included (Fig. 2). It should be noted that the reference lists of the reviews obtained with this search strategy were checked to ensure that all research articles had been included in the systematic analysis.

Fig. 2.

Flow diagram of the study selection process for inclusion in the systematic review according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Created with biorender.com.

Fig. 2.

Flow diagram of the study selection process for inclusion in the systematic review according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Created with biorender.com.

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Study Selection

After removing duplicates, search results were screened by two independent authors (A.U.R. and M.I.Q.-V.) based on their title and abstract. References not meeting the inclusion criteria were excluded. Afterward, candidate articles were full text read autonomously by the same two authors, to ensure that they fulfilled the rest of the inclusion criteria. Any discrepancies about the inclusion or exclusion of articles were discussed and resolved by a third independent reviewer (A.F.G.).

In vivo Models

In recent decades, there has been an increase in the use of animals in dermatological research which has allowed better understanding of certain pathophysiological mechanisms of the skin, leading to the emergence of potential therapeutic targets. Among these, the most used model is based on rodents, due to their availability, easy handling, similarities with humans, possibility of being genetically modified and short lifespan compared to other larger mammals [13]. Other animal models such as zebrafish have also been used. Since psoriasis is a complex disease, a large number of animal models have been investigated, each based on a different pathogenic mechanism. Although all the models used to date are mentioned, this review focuses on chemically induced models as they have appeared most frequently during the systematic search (Table 1).

Table 1.

In vivo models of psoriasis disease

Authors and publication dateIn vivo modelModel creationObjectivePsoriasis hallmarksOutcomes
Guo, et al. [22] (2021) Chemically induced model with IMQ Topical treatment of male BALB/c mice (8–12 weeks old) → 5% IMQ cream on the shaved dorsal skin for 6 consecutive days, once daily, prior to the experimental period To elucidate the magnolol mechanism of action on psoriasis ↑TEWL = ↓Epithelial Function Magnolol restores the TEWL value, activates the expression of the PPAR-γ protein in the epidermis, and inhibits the expression of IL-23, IL-1β, IL-6, TNF-α, and INF-γ 
Silvery scales, erythema, and dry skin 
Epidermal acanthosis, parakeratosis, tortuous capillary dilatation in dermis, and infiltration of various inflammatory cells 
↑Cytokine expression levels (IL-17A, IL-23, IL-1β, IL-6, TNF-α, and IFN-γ) 
Suzuki et al. [23] (2021) Chemically induced model with IMQ Topical treatment of male and female hairless HRS/J mice (6–8 weeks old) →62.5 mg of IMQ cream was topically applied on the back of each animal twice a day for 4 consecutive days To evaluate the efficacy of a delivery system for siRNA based on hybrid PLNs and combined with PCI as a topical treatment for psoriasis Inflammation and erythema ↑Penetration of the compound 
↑Epidermis thickness and leukocyte infiltration ↓Psoriatic signs when irradiation was applied 
Scaling Selective treatment as the formulation is applied only to the inflamed area along with a local light application 
Sun et al. [24] (2021) Chemically induced model with IMQ Topical treatment of male BALB/c mice (6 weeks old) → cream application on the shaved dorsal skin once a day for 7 consecutive days To investigate the role of BRD4 in affecting the psoriatic KTs and the role of JQ1 in decreasing inflammation Epidermal hyperplasia, abnormally thickened, hyperplasia of dermal collagen fibers and dense infiltration of dermal inflammatory cells JQ1 treatment alleviates psoriatic lesions by suppressing inflammation and promoting KTs apoptosis 
Erythema, induration and desquamation 
↑Ki-67 expression levels (cell proliferation marker) It inhibited the MAPK signaling pathway 
↑Inflammatory factors serum levels (IFN-γ, IL-8, and IL-6) 
↑bcl-2 prevents cells from entering apoptosis BRD4 participates in the regulation of KT proliferation and inflammation through the MAPK pathway 
↓bax, cleaved caspase 3/total caspase 3, and cleaved caspase 9/total caspase 9 expression 
↑p-p38/p38, p-JNK/JNK and p-ERK/ERK (MAPK pathway-related proteins) expression 
Martínez-Morcillo et al. [25] (2021) Zebrafish mutant model 1) spint1ahi2217Tg/hi2217Tg Zebrafish psoriasis model with a hypomorphic mutation of spint1a (allele hi2217), which encodes the SP inhibitor, kunitz-type, 1a To investigate the role played by NAD+ and PAR metabolism in skin oxidative stress and inflammation Spint1a-deficient larvae show neutrophil infiltration in the skin, ↑NFKB transcriptional activity (essential transcription factor in psoriasis), ↑ROS levels related to skin inflammation and KT hyperproliferation Hyperactivation of PARP1 in response to ROS-induced DNA damage together with NAD+ derived from NAMPT mediates cell inflammation through parthanate pathway death. NAMPT, PARP1, and AIFM1 as potential therapeutic target to treat inflammatory skin diseases. In fact, mutant larvae treated with NAMPT and PARP1 inhibitors show ↓neutrophil infiltration, ↓NFKB transcriptional activity, ↓ROS levels as well as KT hyperproliferation 
2) atpb1am14/m14 has a loss-of-function mutation in atp1b1a, which encodes the beta subunit of a Na+/K+-ATPase pump atpb1am14/m14mutant zebrafish show skin inflammation and KT hyperproliferation 
Khaledi et al. [26] (2020) Chemically induced model with IMQ Topical treatment of female BALB/c mice (8–11 weeks old) →  50 mg cream application on the shaved dorsal skin for 11 consecutive days To determine the efficacy of Dysidea avara methanolic extract in psoriasis Epidermal acanthosis, hyperkeratosis, increased inflammatory cells in the dermis, and capillary dilatation in dermis Treatment shows a dose-dependent improvement with a ↓IL-22, IL-17A, and TNF-α, ↓inflammation, and ↓ in histopathological signs 
↑Cytokine expression levels (TNF-α, IL-22, and IL-17A) 
↑Permeability by a ↓ in skin cellular integration 
Lee et al. [27] (2020) Chemically induced model with IMQ Topical treatment of female BALB/c mice (8 weeks old) → 5% IMQ cream on the shaved skin for 6 consecutive days To evaluate if a low-fluence CO2 ablative laser could improve skin permeation of siRNA for psoriasis treatment Silvery scales, hyperkeratosis, epidermal acanthosis, and immune-cell dermis infiltration Exposure to low-fluency lasers allows ↑ siRNA penetration through the skin in both control mice and the IMQ model 
↑TEWL = ↓Epithelial Function The silencing of IL-6 expression in the IMQ model using laser-assisted siRNA leads to a 64% reduction in cytokine expression in the psoriatic model 
↑Cytokine expression levels (IL-6, IL-17A, IL-23, and TNF-α) A reduction of plaque, of the expression of specific cytokines, and of the proliferation of KTs is observed 
Broad distribution of Ki-67 throughout the basal layer of the epidermis The use of the laser supposes better effects than if it is not applied 
Ampawong et al. [28] (2020) Chemically induced model with IMQ Topical treatment of rat model → 62.5 mg of IMQ on the dorsal shaved skin daily for 7 consecutive days To evaluate the role of rice crude extract in alleviating the symptoms of psoriasis Redness, silvery scales and thickening, acanthosis, dermatitis, folliculitis, and hyperkeratosis ↓Epidermal thickness, hyperkeratosis, epidermal inflammation, and induction of apoptosis via caspase-3 
↑Caspase-3 levels (marker of apoptosis) and ↓Nrf-2 levels (marker of antioxidative capacity) ↑Anti-inflammatory cytokines and ↓ pro-inflammatory cytokines, chemokines, and antimicrobial peptides 
↓Anti-inflammatory cytokines levels (IL-10 and TGF-β) ↑Nrf-2 expression 
↑Psoriasis biomarkers levels (β-defensin and CCL20) 
Kim et al. [29] (2019) Chemically induced model with IMQ Topical treatment of female C57BL/6 mice (8 weeks old) → 5% IMQ cream on the shaved dorsal skin for 6 consecutive days, once daily To assess the therapeutic potential of hE-MSCs in psoriasis Acanthosis, hyperkeratosis, parakeratosis, and inflammatory infiltration hE-MSCs treatment modulate psoriasis-related symptoms: ↓ the PASI index, erythema and epidermal thickness. It inhibits the expression of cytokines (TNF-α, IFN-α, IFN-γ, IL-27, IL-17A, and IL-23) 
↑Erythema and scarring 
↑Th1 cytokines (TNF-α, IFN-α, IFN-y, and IL-27) and Th17 cytokines (IL-17A and IL-23) 
Spleen hypertrophy as systemic effect 
Fratoddi et al. [30] (2019) Chemically induced model with IMQ Topical treatment of C57BL/6 mice (8 weeks old) → 5% IMQ cream on the shaved dorsal skin for 6 consecutive days, once daily To evaluate the effects of AuNPs-3MPS@MTX topically administered in psoriasis Erythema, thickening, redness, and silvery scales Treatment with AuNPs-3MPS@MTX leads to a ↓in erythema, epidermal thickness, parakeratosis, hyperkeratosis, keratinocyte hyperproliferation, and inflammatory infiltration 
Acanthosis, hyperkeratosis, parakeratosis, and inflammatory cell infiltration in both dermis and epidermis 
Hyperproliferation markers → ↑ Ki-67, K6 expression levels 
Tang et al. [31] (2018) Chemically induced model with IMQ Topical treatment of male C57BL/6 mice (8–12 weeks old) → 5% IMQ cream on the shaved dorsal skin for 7 consecutive days To investigate the therapeutic effects of CTS on psoriasis and to explore the underlying mechanisms Severe plaque, epidermal acanthosis, and increased inflammatory cells in the dermis CTS treatment causes ↓acanthosis, ↓ the severity of plaque formation, ↓PCNA (a marker strictly associated with cell proliferation), and ↓phosphorylated STAT3 
↑Phosphorylated STAT3 levels (key component in KT proliferation) 
Pischon et al. [32] (2017) Chemically induced model with IMQ Topical treatment of male BALB/c mice (6–8 weeks old) → 5% IMQ cream on the shaved skin and the right ear for 7 consecutive days To investigate dermal penetration and biological effects of dendritic CMS-NCs in psoriasis Erythema, silvery scales, and dry skin CMS-NCs were localized to the SC of the epidermis with very sporadic uptake by Langerhans cells. They enhanced lipophilic compounds penetration into the epidermis and were biocompatible to both control and psoriasis mice 
↑TEWL = ↓Epithelial Function 
Epidermal acanthosis, hyperkeratosis, parakeratosis, and inflammatory cell infiltration in both dermis and epidermis 
Spleen hypertrophy as systemic effect 
Chamcheu et al. [33] (2017) Chemically induced model with IMQ Topical treatment of BALB/c mice (6–8 weeks old) → 5% IMQ cream on the shaved skin and the right ear for 5 consecutive days To identify molecular targets regulated by the antioxidant DEL in the treatment of psoriasis Abnormally thickened epidermis, parakeratosis, hyperkeratosis, epidermal microabscesses, dermal capillary dilation, increased epidermal rete ridges, and marked diffuse infiltration of mixed inflammatory cells Topical treatment of with DEL results in a significant ↓ in epidermal hyperproliferation and thickness, in infiltration of immune cells, in the expression of psoriasis-related cytokines and chemokines, and in the activation of PI3K/Akt and mTOR signal transduction pathway 
↑Proliferation markers levels (Ki-67 y STAT3) 
Epidermal cornification markers (K10, LOR, and IVL) displayed an abnormally broad staining pattern in several KT layers 
↓Critical differentiation-related protein levels (caspase-14, FLG, K10, and AP-1 factors) showing weak and abnormally broad expression patterns 
↑Psoriasis-associated epidermal FABP5 expression levels 
↑Pro- and anti-inflammatory cytokines and chemokines expression levels 
↑Chemoattractant protein expression (MIP-1α, MIP-1β, and MIP-2) of neutrophils and T cells 
Steinckwich et al. [34] (2015) Chemically induced model with IMQ Topical treatment of male conditional KO mice lacking STIM1 in cells of myeloid lineage (8–12 weeks old) → 5% IMQ cream on the shaved skin for 5 consecutive days To investigate the involvement of STIM1 in neutrophil chemotaxis during chronic psoriatic inflammation Redness and scales resulting from desquamation and crust formation. Acanthosis, pustule formation, hyperkeratosis, parakeratosis hypo- and hypergranulosis of epidermis, and inflammation STIM1 KO mice have less neutrophil infiltration in the epidermis than controls. Chemoattractant production and macrophage migration were not altered. It had faster reversal of psoriatic plaques 
Inflammatory cells infiltrate into the epidermis 
↑Cytokines and Chemokines Expression Levels (CXCL1, CXCL2, IL-17A, IL-22, and IL-23A) 
Carretero et al. [35] (2013) Xenotransplantation Model Cells isolated from biopsies, healthy donors, and patients with psoriasis together with their blood are used to make this model, obtaining a skin graft. It is placed on the back of immunodeficient female NMRI-nu mice (6–8 weeks old). After this, cytokines IL-17 and IL-22, or subpopulations of T lymphocytes, are injected intradermally into the graft. Tape-stripping is required To establish a skin-humanized mouse model consisting in bioengineered human skin grafted onto immunodeficient mice Epidermis → elongation and fusion of rete ridges, acanthosis, parakeratosis, and partial loss of the granular layer This strategy allows the generation of a large number of mice grafted with a significant and homogeneous area of human skin derived from a single donor. They show that it is possible to generate the model from healthy donors whose samples are easier to obtain than if we work only with patients. The possibility of generating a model from the use of KTs, HFs and immune cells isolated from patients represents an opportunity to overcome the differences between people in the efficacy of the treatment, allowing a personalized treatment 
Dermis → inflammatory cells infiltration increased vascularity and dilated capillaries 
↑IVL and ↓LOR expression levels 
↑K6 and K17 levels (hyperproliferative epidermis) + ↓K1 levels (differentiation marker) 
↑Protein S100A7 (psoriasin) induction 
Authors and publication dateIn vivo modelModel creationObjectivePsoriasis hallmarksOutcomes
Guo, et al. [22] (2021) Chemically induced model with IMQ Topical treatment of male BALB/c mice (8–12 weeks old) → 5% IMQ cream on the shaved dorsal skin for 6 consecutive days, once daily, prior to the experimental period To elucidate the magnolol mechanism of action on psoriasis ↑TEWL = ↓Epithelial Function Magnolol restores the TEWL value, activates the expression of the PPAR-γ protein in the epidermis, and inhibits the expression of IL-23, IL-1β, IL-6, TNF-α, and INF-γ 
Silvery scales, erythema, and dry skin 
Epidermal acanthosis, parakeratosis, tortuous capillary dilatation in dermis, and infiltration of various inflammatory cells 
↑Cytokine expression levels (IL-17A, IL-23, IL-1β, IL-6, TNF-α, and IFN-γ) 
Suzuki et al. [23] (2021) Chemically induced model with IMQ Topical treatment of male and female hairless HRS/J mice (6–8 weeks old) →62.5 mg of IMQ cream was topically applied on the back of each animal twice a day for 4 consecutive days To evaluate the efficacy of a delivery system for siRNA based on hybrid PLNs and combined with PCI as a topical treatment for psoriasis Inflammation and erythema ↑Penetration of the compound 
↑Epidermis thickness and leukocyte infiltration ↓Psoriatic signs when irradiation was applied 
Scaling Selective treatment as the formulation is applied only to the inflamed area along with a local light application 
Sun et al. [24] (2021) Chemically induced model with IMQ Topical treatment of male BALB/c mice (6 weeks old) → cream application on the shaved dorsal skin once a day for 7 consecutive days To investigate the role of BRD4 in affecting the psoriatic KTs and the role of JQ1 in decreasing inflammation Epidermal hyperplasia, abnormally thickened, hyperplasia of dermal collagen fibers and dense infiltration of dermal inflammatory cells JQ1 treatment alleviates psoriatic lesions by suppressing inflammation and promoting KTs apoptosis 
Erythema, induration and desquamation 
↑Ki-67 expression levels (cell proliferation marker) It inhibited the MAPK signaling pathway 
↑Inflammatory factors serum levels (IFN-γ, IL-8, and IL-6) 
↑bcl-2 prevents cells from entering apoptosis BRD4 participates in the regulation of KT proliferation and inflammation through the MAPK pathway 
↓bax, cleaved caspase 3/total caspase 3, and cleaved caspase 9/total caspase 9 expression 
↑p-p38/p38, p-JNK/JNK and p-ERK/ERK (MAPK pathway-related proteins) expression 
Martínez-Morcillo et al. [25] (2021) Zebrafish mutant model 1) spint1ahi2217Tg/hi2217Tg Zebrafish psoriasis model with a hypomorphic mutation of spint1a (allele hi2217), which encodes the SP inhibitor, kunitz-type, 1a To investigate the role played by NAD+ and PAR metabolism in skin oxidative stress and inflammation Spint1a-deficient larvae show neutrophil infiltration in the skin, ↑NFKB transcriptional activity (essential transcription factor in psoriasis), ↑ROS levels related to skin inflammation and KT hyperproliferation Hyperactivation of PARP1 in response to ROS-induced DNA damage together with NAD+ derived from NAMPT mediates cell inflammation through parthanate pathway death. NAMPT, PARP1, and AIFM1 as potential therapeutic target to treat inflammatory skin diseases. In fact, mutant larvae treated with NAMPT and PARP1 inhibitors show ↓neutrophil infiltration, ↓NFKB transcriptional activity, ↓ROS levels as well as KT hyperproliferation 
2) atpb1am14/m14 has a loss-of-function mutation in atp1b1a, which encodes the beta subunit of a Na+/K+-ATPase pump atpb1am14/m14mutant zebrafish show skin inflammation and KT hyperproliferation 
Khaledi et al. [26] (2020) Chemically induced model with IMQ Topical treatment of female BALB/c mice (8–11 weeks old) →  50 mg cream application on the shaved dorsal skin for 11 consecutive days To determine the efficacy of Dysidea avara methanolic extract in psoriasis Epidermal acanthosis, hyperkeratosis, increased inflammatory cells in the dermis, and capillary dilatation in dermis Treatment shows a dose-dependent improvement with a ↓IL-22, IL-17A, and TNF-α, ↓inflammation, and ↓ in histopathological signs 
↑Cytokine expression levels (TNF-α, IL-22, and IL-17A) 
↑Permeability by a ↓ in skin cellular integration 
Lee et al. [27] (2020) Chemically induced model with IMQ Topical treatment of female BALB/c mice (8 weeks old) → 5% IMQ cream on the shaved skin for 6 consecutive days To evaluate if a low-fluence CO2 ablative laser could improve skin permeation of siRNA for psoriasis treatment Silvery scales, hyperkeratosis, epidermal acanthosis, and immune-cell dermis infiltration Exposure to low-fluency lasers allows ↑ siRNA penetration through the skin in both control mice and the IMQ model 
↑TEWL = ↓Epithelial Function The silencing of IL-6 expression in the IMQ model using laser-assisted siRNA leads to a 64% reduction in cytokine expression in the psoriatic model 
↑Cytokine expression levels (IL-6, IL-17A, IL-23, and TNF-α) A reduction of plaque, of the expression of specific cytokines, and of the proliferation of KTs is observed 
Broad distribution of Ki-67 throughout the basal layer of the epidermis The use of the laser supposes better effects than if it is not applied 
Ampawong et al. [28] (2020) Chemically induced model with IMQ Topical treatment of rat model → 62.5 mg of IMQ on the dorsal shaved skin daily for 7 consecutive days To evaluate the role of rice crude extract in alleviating the symptoms of psoriasis Redness, silvery scales and thickening, acanthosis, dermatitis, folliculitis, and hyperkeratosis ↓Epidermal thickness, hyperkeratosis, epidermal inflammation, and induction of apoptosis via caspase-3 
↑Caspase-3 levels (marker of apoptosis) and ↓Nrf-2 levels (marker of antioxidative capacity) ↑Anti-inflammatory cytokines and ↓ pro-inflammatory cytokines, chemokines, and antimicrobial peptides 
↓Anti-inflammatory cytokines levels (IL-10 and TGF-β) ↑Nrf-2 expression 
↑Psoriasis biomarkers levels (β-defensin and CCL20) 
Kim et al. [29] (2019) Chemically induced model with IMQ Topical treatment of female C57BL/6 mice (8 weeks old) → 5% IMQ cream on the shaved dorsal skin for 6 consecutive days, once daily To assess the therapeutic potential of hE-MSCs in psoriasis Acanthosis, hyperkeratosis, parakeratosis, and inflammatory infiltration hE-MSCs treatment modulate psoriasis-related symptoms: ↓ the PASI index, erythema and epidermal thickness. It inhibits the expression of cytokines (TNF-α, IFN-α, IFN-γ, IL-27, IL-17A, and IL-23) 
↑Erythema and scarring 
↑Th1 cytokines (TNF-α, IFN-α, IFN-y, and IL-27) and Th17 cytokines (IL-17A and IL-23) 
Spleen hypertrophy as systemic effect 
Fratoddi et al. [30] (2019) Chemically induced model with IMQ Topical treatment of C57BL/6 mice (8 weeks old) → 5% IMQ cream on the shaved dorsal skin for 6 consecutive days, once daily To evaluate the effects of AuNPs-3MPS@MTX topically administered in psoriasis Erythema, thickening, redness, and silvery scales Treatment with AuNPs-3MPS@MTX leads to a ↓in erythema, epidermal thickness, parakeratosis, hyperkeratosis, keratinocyte hyperproliferation, and inflammatory infiltration 
Acanthosis, hyperkeratosis, parakeratosis, and inflammatory cell infiltration in both dermis and epidermis 
Hyperproliferation markers → ↑ Ki-67, K6 expression levels 
Tang et al. [31] (2018) Chemically induced model with IMQ Topical treatment of male C57BL/6 mice (8–12 weeks old) → 5% IMQ cream on the shaved dorsal skin for 7 consecutive days To investigate the therapeutic effects of CTS on psoriasis and to explore the underlying mechanisms Severe plaque, epidermal acanthosis, and increased inflammatory cells in the dermis CTS treatment causes ↓acanthosis, ↓ the severity of plaque formation, ↓PCNA (a marker strictly associated with cell proliferation), and ↓phosphorylated STAT3 
↑Phosphorylated STAT3 levels (key component in KT proliferation) 
Pischon et al. [32] (2017) Chemically induced model with IMQ Topical treatment of male BALB/c mice (6–8 weeks old) → 5% IMQ cream on the shaved skin and the right ear for 7 consecutive days To investigate dermal penetration and biological effects of dendritic CMS-NCs in psoriasis Erythema, silvery scales, and dry skin CMS-NCs were localized to the SC of the epidermis with very sporadic uptake by Langerhans cells. They enhanced lipophilic compounds penetration into the epidermis and were biocompatible to both control and psoriasis mice 
↑TEWL = ↓Epithelial Function 
Epidermal acanthosis, hyperkeratosis, parakeratosis, and inflammatory cell infiltration in both dermis and epidermis 
Spleen hypertrophy as systemic effect 
Chamcheu et al. [33] (2017) Chemically induced model with IMQ Topical treatment of BALB/c mice (6–8 weeks old) → 5% IMQ cream on the shaved skin and the right ear for 5 consecutive days To identify molecular targets regulated by the antioxidant DEL in the treatment of psoriasis Abnormally thickened epidermis, parakeratosis, hyperkeratosis, epidermal microabscesses, dermal capillary dilation, increased epidermal rete ridges, and marked diffuse infiltration of mixed inflammatory cells Topical treatment of with DEL results in a significant ↓ in epidermal hyperproliferation and thickness, in infiltration of immune cells, in the expression of psoriasis-related cytokines and chemokines, and in the activation of PI3K/Akt and mTOR signal transduction pathway 
↑Proliferation markers levels (Ki-67 y STAT3) 
Epidermal cornification markers (K10, LOR, and IVL) displayed an abnormally broad staining pattern in several KT layers 
↓Critical differentiation-related protein levels (caspase-14, FLG, K10, and AP-1 factors) showing weak and abnormally broad expression patterns 
↑Psoriasis-associated epidermal FABP5 expression levels 
↑Pro- and anti-inflammatory cytokines and chemokines expression levels 
↑Chemoattractant protein expression (MIP-1α, MIP-1β, and MIP-2) of neutrophils and T cells 
Steinckwich et al. [34] (2015) Chemically induced model with IMQ Topical treatment of male conditional KO mice lacking STIM1 in cells of myeloid lineage (8–12 weeks old) → 5% IMQ cream on the shaved skin for 5 consecutive days To investigate the involvement of STIM1 in neutrophil chemotaxis during chronic psoriatic inflammation Redness and scales resulting from desquamation and crust formation. Acanthosis, pustule formation, hyperkeratosis, parakeratosis hypo- and hypergranulosis of epidermis, and inflammation STIM1 KO mice have less neutrophil infiltration in the epidermis than controls. Chemoattractant production and macrophage migration were not altered. It had faster reversal of psoriatic plaques 
Inflammatory cells infiltrate into the epidermis 
↑Cytokines and Chemokines Expression Levels (CXCL1, CXCL2, IL-17A, IL-22, and IL-23A) 
Carretero et al. [35] (2013) Xenotransplantation Model Cells isolated from biopsies, healthy donors, and patients with psoriasis together with their blood are used to make this model, obtaining a skin graft. It is placed on the back of immunodeficient female NMRI-nu mice (6–8 weeks old). After this, cytokines IL-17 and IL-22, or subpopulations of T lymphocytes, are injected intradermally into the graft. Tape-stripping is required To establish a skin-humanized mouse model consisting in bioengineered human skin grafted onto immunodeficient mice Epidermis → elongation and fusion of rete ridges, acanthosis, parakeratosis, and partial loss of the granular layer This strategy allows the generation of a large number of mice grafted with a significant and homogeneous area of human skin derived from a single donor. They show that it is possible to generate the model from healthy donors whose samples are easier to obtain than if we work only with patients. The possibility of generating a model from the use of KTs, HFs and immune cells isolated from patients represents an opportunity to overcome the differences between people in the efficacy of the treatment, allowing a personalized treatment 
Dermis → inflammatory cells infiltration increased vascularity and dilated capillaries 
↑IVL and ↓LOR expression levels 
↑K6 and K17 levels (hyperproliferative epidermis) + ↓K1 levels (differentiation marker) 
↑Protein S100A7 (psoriasin) induction 

Akt Protein kinase B, AuNPs-3MPS@MTX, Gold nanoparticles with 3-mercapto-1-propanesulfonate and methotrexate; Bax, Bcl-2-associated X protein; Bcl-2, B cell lymphoma 2 family of regulator proteins; BRD4, Bromine domain protein 4; CCL20 C-C, motif chemokine ligand 20; CTS, cryptotanshinone; DEL, delphinidin; ERK, extracellular signal-regulated kinase; FABP5, fatty acid-binding protein 5; FLG, filaggrin; HFs, human fibroblasts; hE-MSCs, human embryonic stem cell-derived mesenchymal stem cells; IL, interleukin; IMQ, imiquimod; INF,-γ, interferon γ; IVL, involucrin; JNK, Jun N-Terminal Kinase; JQ1, BRD4 inhibitor; K, keratin; KO, knock-out; KTs, keratinocytes; LOR, loricrin; MAPK, mitogen-activated protein kinase;MCP-3, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; mTOR, mammalian target of rapamycin; NAD+, nicotinamide adenine dinucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NFKB, nuclear factor-κB; Nrf-2, nuclear factor erythroid 2-related factor 2; p38, mitogen-activated protein kinase; p65, REL-associated protein, PARP1, poly-ADP-ribose polymerase 1; PAR, poly(ADP)-ribosylation; PASI, psoriasis area index; PCI, photochemical internalization; PCNA, proliferating cell nuclear antigen; PI3K, phosphoinositide 3-kinases; PLNs, polymer-lipid nanoparticles; PPAR-γ, peroxisome proliferator-activated receptor gamma; ROS, reactive oxygen species; siRNA, small interfering RNA; STAT3, signal transducer and activator of transcription 3 gene; STIM1, stromal interaction molecule 1; TGF-β, transforming growth factor β; TEWL, transepidermal water loss; TNF-α, tumor necrosis factor α.

Spontaneous Models

The first animals used as psoriasis models arose from spontaneous mutations that gave rise to the appearance of disease-specific signs such as plaque formation or increased epidermal thickness. The most prominent were homozygous Asebia (Scd1ab/Scd1ab), chronic proliferative dermatitis (Sharpincpdm/Sharpincpdm), and autosomal recessive mutation in flaky skin mice (Ttcfsn/Ttcfsn) [36].

Briefly, Asebia mice were the first model reported in 1965. They lack sebaceous glands, so they show scaly skin, increased vascularization, hyperproliferation of KTs that produces acanthosis, dermal inflammation, and collagen and elastin alterations [36]. The chronic proliferative dermatitis model is caused by a spontaneous mutation that produces progressive inflammation in various organs, resulting in vasodilation, hyperkeratosis, scaly skin, and accumulation of immune cells at all levels of the skin (eosinophils, macrophages, and mast cells) [36]. Finally, flaky skin mice exhibit parakeratosis, epidermal hyperplasia, dilated blood vessels, and infiltration of immune cells in both the epidermis (neutrophils) and dermis (leukocytes and macrophages) [36, 37].

Due to the lack of T cells and the poor response of these models to certain drugs for disease treatment, the use of spontaneous models has been limited [38]. Therefore, these models have become obsolete with the appearance of new scientific approaches.

Genetically Modified Models

Psoriasis is a multifactorial disorder involving a large number of genes. To break down its pathogenesis, most genetically modified models (also known as transgenic) are based on the manipulation of a single gene. The aim was to define its involvement in disease development [36, 37]. In most rodents belonging to this category, specific genetic alterations have been made, resulting in the overexpression or loss of function (knock-out, KO) of a particular protein in different cell types or tissues [36]. The following are some of the models in this category, which are divided according to the modification objective.

Epidermal Keratinocytes or Cytokines. Different models overexpressing KT-specific genes can be found under the control of the K5 or K14 promoter. Mice under the control of the K5 promoter include but are not limited to, K5.Stat3C mouse, K5.TGF-β1 mouse, K5-IκBα-deficient mouse, and K5-IL-17C mouse [18]. The K5.Stat3C model in which constitutive expression of the signal transducer and activator of transcription 3 (STAT3) gene in KTs occurs is highlighted. This is a transcription factor that is activated in psoriatic KTs. In this model, the psoriatic phenotype arises spontaneously when the epidermal barrier is damaged by applying adhesive tape. Its use has demonstrated that STAT3 inhibition is involved in resolution of the phenotype in these mice, suggesting a possible treatment [10, 36, 37].

On the other hand, overexpression of epidermal cytokines occurs under the control of the K14 promoter. Some of the mice included are K14-IL-17Aind/+ mouse, K14-p40 mouse, K14-TNF-α mouse, K14-IL-20 mouse, and K14-KGF mouse. An example of the advances achieved thanks to these is the case of the K14-IL-17Aind/+ mouse where an increase of neutrophils and monocytes was observed in the blood, suggesting that IL-17A expression participates in the circulation of immune cells to the bone marrow [36].

Immune Cells. This group includes the hypomorphic PL/J/CD18 mouse developed in the early 1990s, which has mutations in the β2 integrins (responsible for cell-cell interaction in inflammatory processes) of leukocytes. Its use has provided insight into the role of macrophages over the course of the disease [38].

Vascular Endothelium. Erythema is a typical clinical sign of psoriasis as a consequence of dilated blood vessels and increased angiogenesis. This increased vascularity leads to enhanced infiltration of immune cells into psoriatic lesions. Hence, there is a need for other approaches to modify specific growth factors such as vascular endothelial growth factor (VEGF), which is involved in blood vessel formation [10]. The K14-VEGF model overexpresses the VEGF gene in the mouse epidermis through the K14 promoter. This spontaneously develops psoriatic features over the years, such as hyperkeratosis, parakeratosis, increased immune cells, and angiogenesis. The use of this model suggests a combined Th1 and Th17 response over the course of the disease, exhibited as an increase in pro-inflammatory cytokines and chemokines systemically and locally [36, 37]. In addition, KO mice have been generated for the epidermal VEGF receptor to investigate its role in maintaining homeostasis in terms of epithelial barrier permeability [39]. Therefore, this would be an interesting model to study drugs targeting angiogenic mechanisms.

Some of the limitations of genetically modified mouse models are that they can cause early embryonic death, affect the expression of more than one gene or cause unwanted expression of the gene of interest. Moreover, they are costly in terms of time and money [40]. However, the role of certain cytokines, growth factors and mediators of the inflammatory response during the development of the disease has been clarified using these models [38].

Induced Models

This group can be subdivided into two: (a) those obtained by injecting cytokines and (b) those obtained by applying chemical products. Although infrequently applied individually, skin inflammation could also be induced by breaking the epidermal barrier by repeatedly using adhesive tape to cause sequential removal of the SC layers [40].

Induced by Intradermal Injection of Pro-Inflammatory Cytokines. The model created by intradermal injection of IL-23 into the mouse ear is highlighted. Its injection results in activation of the Th17 pathway, leading to greater infiltration of immune cells, increased vascularization, and KT proliferation. This results in hyperplasia, parakeratosis, and acanthosis [10, 38]. This model is very useful for studying drugs targeting the IL-23/Th17 pathway which is essential in the development of this disorder in humans. Another model based on the injection of IL-21 suggests that this cytokine induces IFN-γ-dependent inflammation (unlike IL-23 which is mediated by TNF-α), contributing to the understanding of the role of IL-21 in the inflammatory process [36].

Chemically Induced. Chemically induced models refer almost exclusively to those generated by daily topical application (5–7 days) of the compound imiquimod (IMQ). Due to its ease of obtention and lower cost, the use of these models has increased in recent years, becoming the main in vivo model for preclinical studies on psoriasis. IMQ is a synthetic agonist of the Toll-like receptor (TLR) 7/8 of monocytes, macrophages and DCs, resulting in the production of pro-inflammatory cytokines and chemokines. This results in the entry of inflammatory cells into the application site, leading to a psoriatic phenotype [10, 34].

Using this model, Kim et al. [29] studied the therapeutic effect of human embryonic stem cell-derived mesenchymal stem cells (hE-MSCs), resulting in an improvement of typical signs of the disease (e.g., reduction of epidermal thickness) and indicating that these cells could be a potential treatment. Sun et al. [24] evaluated the role of bromine domain protein 4 (BRD4) in psoriatic KTs. As a result, they obtained increased expression of this protein that was reduced after injecting an inhibitor. At the same time, this caused a reduction in psoriatic signs (suppressing inflammation and causing KT apoptosis). In addition, there was inhibition of the mitogen-activated protein kinase signaling pathway, suggesting that BRD4 is involved in KT proliferation from this pathway during psoriasis. Therefore, this protein becomes a potential therapeutic target.

Nevertheless, these models also have limitations that should be taken into account: (a) both (cytokine injection and chemically induced) are models of acute inflammation, whereas in humans this disorder is characterized by chronic disease. In addition, animals tend to scratch at the application site which may increase the thickening of the dermis; (b) IMQ model produces a different inflammatory and immune response to humans, which is not limited to the skin; (c) IMQ application for longer than 2 weeks can lead to death because it causes dehydration accompanied by a decrease in body weight; (d) depending on the mouse strain used, there are other intrinsic limitations related to gene expression. For example, the C57BL/6 strain has more human-like gene expression than the BALB/c strain; (e) finally, comorbidities typical of the disease in humans such as psoriatic arthritis cannot be observed in either model [36].

There are other limitations related to the lack of standardized protocols for generating models by dermal injection or chemical induction. For example, as reflected in Table 1, there are variations between authors in the frequency and duration of treatment, product manufacturer, dosage, and even the type of animal and its conditioning [40].

Xenotransplanted or Humanized Models

Bearing in mind that the common goal is to increase the possibility of transferring the results obtained to the clinical environment, studies should be carried out on a humanized model that has both immune cells and skin of human origin. Xenotransplantation models have emerged in response to this need. Two mouse strains are commonly used to obtain them: the severe combined immunodeficiency mouse and the AGR129 mouse. Both allograft incorporation without rejection due to the absence of lymphocytes B and T, and AGR129 mice lack type I and II IFN receptors, resulting in altered natural killer cell activity [36]. Briefly, regardless of the strain used, the model is based on the removal of donor psoriatic skin and its placement on the back of the mouse. By using psoriatic biopsies that have inflammatory cells in them, ex vivo stimulation is not necessary, which is an advantage over other models. Similarly, the model could be obtained using healthy skin from a psoriatic patient grafted onto a mouse, together with the injection of autologous peripheral blood mononuclear cells. In this way, healthy skin will acquire a psoriatic phenotype. Therefore, this model allows the mechanisms involved in the development of a psoriatic plaque to be studied [10, 37].

Limitations of these models include low availability and heterogeneity of psoriatic skin and their costliness in terms of both time and money resulting in low yield [10]. In order to overcome these limitations, Guerrero-Aspizua et al. [35, 41] developed a mouse model with humanized skin, making use of tissue engineering. In this way, a large number of grafted mice can be developed with a homogeneous sample based on a fibrin matrix on which KTs and human fibroblasts (HFs) previously isolated from a skin biopsy have been assembled (Table 1). Furthermore, they demonstrated the possibility of obtaining a psoriatic phenotype, whether the initial biopsy belongs to skin from healthy patients or skin from patients with the disease, after adding specific cytokines and/or lymphocyte populations together with a small disruption of the epidermal barrier using adhesive tape. These models bring us ever closer to the possibility of personalized treatment.

Other Animal Models: Zebrafish

Although the mouse has been the most widely used model in research, the use of zebrafish as an animal model has recently been extended in certain basic research. This is due to the similarity with the human genome, easy genetic manipulation, embryonic transparency, and above all, the rapid embryonic development along with the high number of offspring. In addition since they have a less developed neurological system than mice, it is believed that the perception of pain and stress generated in the experiments will be lower for these animals [13].

The use of zebrafish has been reported by Martínez-Morcillo et al. [29] (Table 1). Briefly, they use two zebrafish mutant models (spint1ahi2217Tg/hi2217Tg and atpb1am14/m14) to study the involvement of nicotinamide adenine dinucleotide (NAD+) in chronic inflammation. After appropriate experiments, they demonstrate that inhibition of nicotinamide phosphoribosyltransferase and poly-ADP-ribose polymerase 1 (PARP1) reduces oxidative stress, inflammation, KT hyperproliferation, and cell death in these models.

Throughout this section, it has been demonstrated that psoriatic animal models are a useful approach for the in vivo study of psoriasis. However, in recent years, for ethical reasons the 3R guidelines (reduction, refinement, and replacement of animals in experimentation) emerged within the seventh amendment of the EU Cosmetics Directive 76/768/EEC [42]. This has led to the appearance of alternative methods such as cocultures and three-dimensional (3D) systems that can replicate, as far as possible, the pathophysiology of human psoriatic skin [43].

In vitro Models

In vitro models for psoriasis, with structural and immune components, have been developed in the form of two-dimensional (2D) culture systems and 3D skin constructs. Regarding 2D models, single cell and coculture monolayers can be found. Reconstructed human epidermal equivalent (RHE) and full-thickness skin equivalents (FTSE) are the main 3D models developed for mimicking psoriasis. The following sections will analyze the composition, development, and applications of in vitro models.

2D Models

Single cell and coculture monolayers represent the simplest ways to model psoriasis and they are mainly composed of KTs. These KTs can come from primary cultures or from immortalized lines. Immortalized KT lines include HaCaT cells [24, 44‒47] and N/TERT1, N/TERT2G [48]. Coculture monolayer consists of co-culture of KTs with immune cells. One example of this is the coculture of HaCaT cells with human leukemia monocytic cell line (THP-1) [44]. These KT-T cell coculture systems suggested that KT-T cell communication can recruit immune cells into the skin by secreting chemokines as well as regulating T-cell differentiation [49].

Different strategies have been developed in order to induce psoriasis in these models. These cytokines include Th1 cytokines (TNF-α, IL-6, and IL-1α) or Th17 cytokines (IL-17 and IL-22). The addition of the cytokine mix has successfully resulted in the development of specific characteristics of psoriatic skin. For instance, Bochenska et al. [44] showed how in the single cell monolayers of HaCaT cell line and primary normal human epidermal keratinocytes (NHEKs), these cytokines activate KTs and the psoriatic phenotype is obtained. Other strategies to induce psoriasis include the addition of IMQ serum-free medium (SFM) supplemented with serum from psoriatic patients [44], phorbol 12-myristate 13-acetate (PMA), lipopolysaccharide, IFN-γ [44], and 12-O-tetradecanolylphorbol 13-acetate [33, 46].

These approaches are used to establish an in vitro inflammatory psoriatic model and to evaluate how different molecules or compounds affect the psoriatic phenotype. Among the different molecules tested in psoriatic 2D models, BRD4, fisetin, brazilin, delphinidin (DEL), liposome-encapsulated RNAi molecules, bakusylan, and Y-27632 can be found. The results of the research evaluating the effect of these molecules on psoriatic 2D models are included in Table 2.

Table 2.

In vitro 2D models of psoriasis disease

Authors and publication dateIn vitro modelCompositionObjectiveOutcomes
CellsPsoriasis induction
Bochénska et al. [44] (2021) KT monolayers HaCaT cell line monolayer and primary NHEKs monolayer Cytokine mix (IL-1α, IL-17A, IL-22, oncostatin M, and TNF-α) or IMQ or SFM supplemented with serum from psoriatic patients To establish an in vitro inflammatory psoriatic model, recapitulating specific characteristics of lesional psoriatic skin The results most reflecting the psoriatic phenotype were 5MIX at Ca2+≤ 0.1 mm for HaCaT cell line and 5MIX at Ca2+ = 2 mm for NHEKs 
KT coculture Coculture of HaCaTs with THP-1 PMA/LPS/IFN-γ IMQ alone provides an incomplete picture of the disease in HaCaTs and in NHEKs. Incubation with 1% serum for 24 h is sufficient to obtain the psoriasis phenotype 
Regarding coculture, the psoriasis phenotype was obtained for HaCaT cells cultivated with THP-1 stimulated with 30 ng/mL PMA and 10 ng/mL LPS 
Sun et al. [24] (2021) KT monolayer HaCaT cells monolayer TNF-α or IL-17A To investigate the role of BRD4 in affecting the psoriatic KTs ↑BRD4 expression in HaCaT cells induced by TNF-α or IL-17A 
JQ1 ↓the inflammation and proliferation, and ↑ the apoptosis of HaCaT cells induced by TNF-α or IL-17A 
JQ1 ↓the MAPK signaling pathway in HaCaT cells induced by TNF-α or IL-17A 
Chamcheu et al. [46] (2019) KT monolayer Primary NHEKs monolayer IL-22, TNF-α, and TPA To characterize the effects of fisetin in 2D psoriatic skin models Fisetin treatment promotes NHEK differentiation 
It regulates TNF-α-induced activation of the PI3K/Akt/mTOR and MAPK signaling pathways in NHEKs monolayer 
Fisetin pretreatment significantly decreased inactivated and TPA-induced NHEK secretion of pro-inflammatory cytokines 
Choi et al. [45] (2019) KT monolayer HaCaT cells monolayer TNF-α To determine anti-inflammatory activity of brazilin in TNF-α-induced human KTs widely used as a model of psoriatic dermatitis ↓mRNA expression levels of inflammatory cytokines in a concentration-dependent manner 
↓Phosphorylation of I-κB, Akt, and MAPKs 
TNF-α induced inflammation caused reduction of TEER value which was recovered by treatment with brazilin in a concentration-dependent manner 
Chamcheau et al. [33] (2017) KT monolayer Primary NHEKs monolayer IL-22 and TPA To identify molecular targets regulated by DEL in psoriasis DEL reduces the hyperproliferative and activated KT phenotype induced by IL-22 by reducing the activation of PI3Ks and phosphorylation of Akt, mTOR, and PRAS40 and p70S6K 
It also reduces the TPA-induced secretion of the pro-inflammatory cytokines and TGF-α 
Desmet et al. [50] (2017) KT monolayer Primary NHEKs monolayer culture Cytokine mix (IL-1α, IL-6, IL-17A, and TNF-α) To evaluate the efficacy of liposome-encapsulated RNAi suppressing genes encoding key players (IL-22RA1, K17, hBD-2, and TSLP) in psoriasis There is an inferior silencing of K17 when using the mix as compared to the single K17 siRNA. The decrease in TSLP and DEFB4 mRNA levels was comparable to that of the single treatments or even enhanced 
Ma et al. [51] (2017) KT monolayer Epidermal KT progenitors from stratum basale Cytokine mix (IL-17A, IL-22, and TNF-α) To synthesis a novel molecule, bakuchiol salicylate (bakusylan), with a modulatory gene expression profile similar to retinoids Bakusylan inhibited the cytokine-induced shift in KT morphology toward the senescent phenotype by about 60% and has retinoid-like transcription-modulation activity 
Genes ↓by bakusylan tended to have ↑expression in psoriasis lesions, whereas genes ↓by bakusylan showed ↓expression in patients lesions treated with antipsoriatic drugs 
Pfaff et al. [52] (2017) KT monolayer Primary NHEKs monolayer culture IL-17A To address the role of IL-17A in KT differentiation IL-17A activates AMPs and IL-36 cytokines in KT monolayer cultures 
Cytokines of the IL-36 family interfere with KT differentiation 
Smits et al. [48] (2017) KT monolayer N/TERT1, N/TERT2G immortalized KT cell lines Th1 cytokines (TNF-α, IL-6, and IL-1α) or Th17 cytokines (IL-17 and IL-22) To compare N/TERT1 and N/TERT2G cell lines to NHEKs based on epidermal differentiation, response to inflammatory mediators, and the development of normal and inflammatory human epidermal equivalents ↓FLG and LOR (in N/TERT2G keratinocytes this downregulation was significantly stronger as compared to NHEKs) 
Primary NHEKs monolayer culture ↑Psoriasis-related host defense genes PI3 and DEFB4 in both primary and N/TERT KTs 
Henry et al. [47] (2016) KT monolayer Primary NHEKs monolayer IL-36 To explore the biological effects of active IL-36 Active IL-36β induced robust expression of a diverse array of pro-inflammatory cytokines from primary KTs and HaCaT cells 
HaCaT monolayer 
Van den Bogaard et al. [53] (2012) KT monolayer Liquid-nitrogen-stored primary adult KTs IL-1α, TNF-α, and IFN-γ To evaluate the effects of Y-27632 on HSE development Unstimulated KTs showed ↓expression levels of hBD-2, while IL-1b mRNA expression levels were slightly ↑ at 10 and 100 μm Y-27632. KT activation was unaffected by Y-27632 
Y-27632-treated KTs High-passage Y-27632-treated KTs also showed a significant induction of hBD-2 when cultured with 10 μm Y-27632 
Authors and publication dateIn vitro modelCompositionObjectiveOutcomes
CellsPsoriasis induction
Bochénska et al. [44] (2021) KT monolayers HaCaT cell line monolayer and primary NHEKs monolayer Cytokine mix (IL-1α, IL-17A, IL-22, oncostatin M, and TNF-α) or IMQ or SFM supplemented with serum from psoriatic patients To establish an in vitro inflammatory psoriatic model, recapitulating specific characteristics of lesional psoriatic skin The results most reflecting the psoriatic phenotype were 5MIX at Ca2+≤ 0.1 mm for HaCaT cell line and 5MIX at Ca2+ = 2 mm for NHEKs 
KT coculture Coculture of HaCaTs with THP-1 PMA/LPS/IFN-γ IMQ alone provides an incomplete picture of the disease in HaCaTs and in NHEKs. Incubation with 1% serum for 24 h is sufficient to obtain the psoriasis phenotype 
Regarding coculture, the psoriasis phenotype was obtained for HaCaT cells cultivated with THP-1 stimulated with 30 ng/mL PMA and 10 ng/mL LPS 
Sun et al. [24] (2021) KT monolayer HaCaT cells monolayer TNF-α or IL-17A To investigate the role of BRD4 in affecting the psoriatic KTs ↑BRD4 expression in HaCaT cells induced by TNF-α or IL-17A 
JQ1 ↓the inflammation and proliferation, and ↑ the apoptosis of HaCaT cells induced by TNF-α or IL-17A 
JQ1 ↓the MAPK signaling pathway in HaCaT cells induced by TNF-α or IL-17A 
Chamcheu et al. [46] (2019) KT monolayer Primary NHEKs monolayer IL-22, TNF-α, and TPA To characterize the effects of fisetin in 2D psoriatic skin models Fisetin treatment promotes NHEK differentiation 
It regulates TNF-α-induced activation of the PI3K/Akt/mTOR and MAPK signaling pathways in NHEKs monolayer 
Fisetin pretreatment significantly decreased inactivated and TPA-induced NHEK secretion of pro-inflammatory cytokines 
Choi et al. [45] (2019) KT monolayer HaCaT cells monolayer TNF-α To determine anti-inflammatory activity of brazilin in TNF-α-induced human KTs widely used as a model of psoriatic dermatitis ↓mRNA expression levels of inflammatory cytokines in a concentration-dependent manner 
↓Phosphorylation of I-κB, Akt, and MAPKs 
TNF-α induced inflammation caused reduction of TEER value which was recovered by treatment with brazilin in a concentration-dependent manner 
Chamcheau et al. [33] (2017) KT monolayer Primary NHEKs monolayer IL-22 and TPA To identify molecular targets regulated by DEL in psoriasis DEL reduces the hyperproliferative and activated KT phenotype induced by IL-22 by reducing the activation of PI3Ks and phosphorylation of Akt, mTOR, and PRAS40 and p70S6K 
It also reduces the TPA-induced secretion of the pro-inflammatory cytokines and TGF-α 
Desmet et al. [50] (2017) KT monolayer Primary NHEKs monolayer culture Cytokine mix (IL-1α, IL-6, IL-17A, and TNF-α) To evaluate the efficacy of liposome-encapsulated RNAi suppressing genes encoding key players (IL-22RA1, K17, hBD-2, and TSLP) in psoriasis There is an inferior silencing of K17 when using the mix as compared to the single K17 siRNA. The decrease in TSLP and DEFB4 mRNA levels was comparable to that of the single treatments or even enhanced 
Ma et al. [51] (2017) KT monolayer Epidermal KT progenitors from stratum basale Cytokine mix (IL-17A, IL-22, and TNF-α) To synthesis a novel molecule, bakuchiol salicylate (bakusylan), with a modulatory gene expression profile similar to retinoids Bakusylan inhibited the cytokine-induced shift in KT morphology toward the senescent phenotype by about 60% and has retinoid-like transcription-modulation activity 
Genes ↓by bakusylan tended to have ↑expression in psoriasis lesions, whereas genes ↓by bakusylan showed ↓expression in patients lesions treated with antipsoriatic drugs 
Pfaff et al. [52] (2017) KT monolayer Primary NHEKs monolayer culture IL-17A To address the role of IL-17A in KT differentiation IL-17A activates AMPs and IL-36 cytokines in KT monolayer cultures 
Cytokines of the IL-36 family interfere with KT differentiation 
Smits et al. [48] (2017) KT monolayer N/TERT1, N/TERT2G immortalized KT cell lines Th1 cytokines (TNF-α, IL-6, and IL-1α) or Th17 cytokines (IL-17 and IL-22) To compare N/TERT1 and N/TERT2G cell lines to NHEKs based on epidermal differentiation, response to inflammatory mediators, and the development of normal and inflammatory human epidermal equivalents ↓FLG and LOR (in N/TERT2G keratinocytes this downregulation was significantly stronger as compared to NHEKs) 
Primary NHEKs monolayer culture ↑Psoriasis-related host defense genes PI3 and DEFB4 in both primary and N/TERT KTs 
Henry et al. [47] (2016) KT monolayer Primary NHEKs monolayer IL-36 To explore the biological effects of active IL-36 Active IL-36β induced robust expression of a diverse array of pro-inflammatory cytokines from primary KTs and HaCaT cells 
HaCaT monolayer 
Van den Bogaard et al. [53] (2012) KT monolayer Liquid-nitrogen-stored primary adult KTs IL-1α, TNF-α, and IFN-γ To evaluate the effects of Y-27632 on HSE development Unstimulated KTs showed ↓expression levels of hBD-2, while IL-1b mRNA expression levels were slightly ↑ at 10 and 100 μm Y-27632. KT activation was unaffected by Y-27632 
Y-27632-treated KTs High-passage Y-27632-treated KTs also showed a significant induction of hBD-2 when cultured with 10 μm Y-27632 

Akt, protein kinase B; AMPs, antimicrobial peptides; BRD4, bromine domain protein 4; DEFB4, β-defensin 4; DEL, delphinidin; FLG, filaggrin; hBD-2, human β-defensin-2; IL, interleukin; IMQ, imiquimod; INF-γ, interferon γ; JQ1, BRD4 inhibitor; K, keratin; KTs, keratinocytes; LPS, lipopolysaccharide; LOR, loricrin; MAPK, mitogen-activated protein kinases; mTOR, mammalian target of rapamycin; NHEK, normal human epidermal keratinocytes; p70S6K, ribosomal protein S6 kinase beta-1; PI3K, phosphoinositide 3-kinases; PMA, phorbol 12-myristate 13-acetate; PRAS40, proline-rich AKT substrate; siRNA, small interfering RNA; TEER, transepithelial electrical resistance; TGF-α, transforming growth factor α; THP-1, human leukemia monocytic cell line; TNF-α, tumor necrosis factor α; TPA12-O, tetradecanolylphorbol 13-acetate; TSLP, thymic stromal lymphopoietin; SFM, serum-free medium.

Briefly, BRD4 expression in HaCaT cells is induced by TNF-α or IL-17A [24]. Fisetin promoted primary NHEK differentiation. It also upregulated the expression of AP-1 transcription factor proteins and regulated IL-22-induced KT proliferation and TNF-α-induced activation of the phosphoinositide 3-kinases (PI3K)/protein kinase B(Akt)/mammalian target of rapamycin and mitogen-activated protein kinase signaling pathways [46]. Brazilin reduced mRNA expression levels of inflammatory cytokines in a concentration-dependent manner [45] and DEL seemed to reduce the hyperproliferative and activated KT phenotype induced by IL-22 [33]. Bakusylan inhibited the cytokine-induced shift in KT morphology toward the senescent phenotype and decreased the expression of genes that tended to have elevated expression in psoriasis [51]. Regarding liposome-encapsulated RNAi molecules, Desmet et al. [50] evaluated the therapeutic efficacy of suppressing genes encoding key players in psoriasis. They found that in KT monolayer, there is an inferior silencing of K17 when using the mix of RNAi molecules as compared to the single K17 small interfering RNA. The decrease in thymic stromal lymphopoietin and DEFB4 mRNA levels was comparable to the single treatments or even enhanced. Finally, Van den Bogaard et al. [53] analyzed the effects of Y-27632, a pharmacological inhibitor of Rho-associated protein kinases on human adult KTs. They stated that Y-27632-treated KTs responded normally to inflammatory stimuli, and could be used to generate human skin equivalents with a psoriatic phenotype.

3D Models

Unlike 2D models, 3D models can accurately reproduce the in vivo characteristics of the human skin in terms of epidermal morphology, differentiation, and barrier function [49]. Regarding structure and composition, three different 3D models can be differentiated. First, RHE comprises the epidermis alone with KTs grown at an air-liquid interface. These substitutes can be developed using primary NHEKs [25, 54], immortalized lines [48, 55], or they can be commercial [51, 56, 57]. However, the most used 3D model to mimic psoriasis is FTSE. They consist of an epidermal and a dermal layer which is closer to the native skin structure. In order to develop FTSE, KTs are seeded on top of dermal-like structures. These structures can be collagen type I gel mixed with HFs [28, 30, 46, 47, 52, 58, 59], de-epidermized dermis (DED) [43, 53, 60] or self-assembled dermal sheets [61‒69]. DED is obtained from donated skin samples which are cut into squares and de-cellularized. To develop self-assembled dermal sheets, dermal HFs are grown to confluence while secreting their own extracellular matrix (ECM) to build a dermal sheet, and KTs are seeded on top of stacked dermal sheets to undergo differentiation and cornification. Once the models are ready, an air-liquid interface is used to achieve epidermal stratification and keratinization. It should be pointed out that commercial FTSE are also available, which are developed with human psoriatic KTs and collagen-contracted HFs cultured to form a multilayered and highly differentiated epidermis [50, 70].

As in the case of 2D models, the most used strategy and the simplest way to induce psoriasis is the addition of relevant cytokines to the culture medium [25, 48, 50‒55, 59, 71]. Other strategies include the use of psoriatic KTs and HFs from psoriatic patients to construct the epidermis and dermis, respectively [28, 55, 61‒63, 65‒69, 72], the addition of activated T cells [46, 58, 64] or the addition of specific molecules such as putrescine [43]. Once the induction of the psoriasis phenotype is achieved, these models have different applications which are summarized in Table 3.

Table 3.

In vitro 3D models of psoriasis disease

Authors and publication dateIn vitro modelCompositionObjectivePsoriasis hallmarksOutcomes
methodpsoriasis induction
Martínez-Morcillo et al. [25] (2021) RHE Primary NHEKs for epidermis development Th17 cytokines IL-17A and IL-22 To investigate the role played by NAD+ and PAR metabolism in skin oxidative stress and inflammation Not described ↑NAMPT transcript levels in psoriatic epidermis 
Pharmacological inhibition of NADPH oxidases with apocynin ↓the mRNA levels of DEFB4, while it did not affect FLG and LOR
Inhibition of NAMPT, PARP, and AIFM1 reduced the transcript levels DEFB4 and S100A8 
Simard et al. [61] (2021) FTSE Self-assembly method Psoriatic HFs and KTs To investigate the effects of ALA on the proliferation and differentiation ↑Epidermal thickness and higher levels of proliferative KTs ↓KT proliferation 
↑Psoriatic substitute epidermal differentiation (↓ FLG and LOR) 
Models: HSE, HSE+ALA, PSE, PSE+ALA ALA was incorporated into the epidermal phospholipids and metabolized into long-chain n-3 polyunsaturated fatty acids 
The kinases 1 and 2 were the most activated after ALA supplementation 
Cardinali et al. [55] (2021) RHE The immortalized human KT cell line Ker-CT was used to generate epidermis Th1/Th17 cytokines, TNF-α, IL-6, IL-1α, and IL-17A To test the safety profile and the biological activity of NPD-0614-13 and NPD-0614-24, two AhR ligands structurally related to FICZ, known to be effective in psoriasis Thickening of the SC and the loss of the granular layer Both ↑epidermal morphology and ↓the SC thickness in psoriatic RHEs 
↓IVL and FLG expressions ↓Psoriasin, hBD-2 and the mRNA expression of all pro-inflammatory cytokines 
FTSE NHEKs and psoriatic HFs harvested from psoriasis lesions. No description of the method Psoriatic HFs ↑ S100A7, hBD-2 and psoriasin expressions The treatment of a 3D psoriatic FTSE with both compounds ↑ the differentiation process (↑SC thickening and expression of FLG) 
Treatment ↓ expression of hBD-2 and the release of pro-inflammatory cytokines IL-6 and IL-8 
Ampawong et al. [28] (2020) FTSE Collagen-based method Psoriatic KTs To evaluate the role of black-colored rice crude extract in alleviating the symptoms of psoriasis ↑Epidermal thickness, acanthosis, hyperkeratosis, and epidermal inflammation ↓Epidermal thickness and 3-caspase, psoriasin, and koebnerisin expression levels 
↑Psoriasin and koebnerisin expressions ↑Antioxidant capacity (Nfr2 expression) 
↑Pro-inflammatory cytokines ↑Caspase-14, FLG and IVL expression 
↓Pro-inflammatory cytokines and ↑IL-4 and TGF-β 
Simard et al. [62] (2020) FTSE Self-assembly method Psoriatic HFs and KTs To evaluate the impact of either CT or ISO on the pathological characteristics of the dermatosis while producing a psoriatic skin model Not described PSE+CT and PSE+ISO → ↑epidermal proliferation 
The hyperproliferation was greater in the epidermis of PSE+CT than PSE+ISO. 
↓FLG, K10, and cAMP ↑IVL in PSE+CT. 
Models: HSE+CT, HSE+ISO, PSE+CT, PSE+ISO. ADCY genes in PSE+CT than in HSE+CT. 
↓ADRB2 was decreased in PSE+CT. 
↑AC9 levels in psoriatic substitutes 
Shin et al. [58] (2020) FTSE Collagen-based method Activated T cells To recapitulate inflammatory skin diseases using patient-specific cells and a physiological in vitro platform that allows for dissecting epidermal and immune cell interactions as well as quantification of T cell migration into the skin in the context of disease progression and drug treatment T cells migrated into the dermis and retained their proliferative state 
Models Th1/Th17-bearing pFTSEs exhibited a ↑expression of K16, a ↓expression of PPP6c, and ↑epidermis, resembling the psoriatic epidermal phenotype and produced ↑concentrations of pro-inflammatory cytokines 
Th1/Th17-bearing psoriatic FTSE (in vitro polarized) CCR6+CLA+ T cell-bearing pFTSEs showed ↑K16 and hBD-2, and ↓PPP6c representing the psoriatic epidermal phenotype 
CCR6+CLA+ T cell-bearing psoriatic FTSE (psoriatic patient T cells) Treatment with neutralizing anti-IL-17A antibodies reversed these markers 
CCR6CLA- T cell-bearing psoriatic FTSE. 
Bélanger et al. [63] (2019) FTSE Self-assembly method Psoriatic HFs and KTs To investigate the antipsoriatic activities of dihydrochalcone derivatives from Populus balsamifera L.buds, known as balsacones ↑Epidermal thickness Standard treatment MTX or balsacones show a significant ↓in the thickness of the living epidermis and IVL and LOR expression seems partially or fully restored, suggesting a normalization of the differentiation process 
Hyperproliferation 
↑IVL expression All have anti-inflammatory and antioxidant potentials 
↓LOR expression 
Chamcheu, JC et al. (2019) [46FTSE Collagen-based method Activated T cells To characterize the effects of fisetin in a 3D psoriasis-like disease model ↑ Epidermal thickness and proliferation Topical application of fisetin modulates psoriasis-like features, suppresses proliferation and mTOR activation and inflammation, and modulates differentiation 
Aberrant expression of differentiation markers 
↑ Psoriasin and IL-17A secretion 
Lorthois et al. [64] (2019) FTSE Self-assembly method Activated T cells To develop and analyze the effect of activated T cells in lesional reconstructed skin models, compared to T cell-free healthy and lesional skin models, to evaluate the impact of T cells on the lesional skin phenotype and on psoriatic key markers At day 21, most lymphocytes migrated within the dermal compartment, while few of them migrated to the epidermis, closely mimicking the in vivo infiltration of T cells in lesional plaques 
The infiltration of activated T cells significantly dramatically increased the thickness of LS at day 21 
Models: HSE, LS, LS+T The addition of T cells ↑the proliferation within the dermal compartment of lesional skin models 
Lesional immunocompetent skin models promoted sustained and chronic inflammation induced by T cells 
T cells are partly responsible for the activation of the STAT1 pathway 
Clarysse et al. [59] (2019) FTSE Collagen-based method IL-17A, IL-22, and TNF-α To address the direct impact of kinase inhibition of the JAK1/3 pathways by tofacitinib on KT immune function and barrier formation in psoriasis Hyperkeratosis, parakeratosis and acantosis Psoriasis-like morphologic features were prevented by tofacitinib compared to sham-treated conditions 
FLG expression was mild preserved by tofacitinib in psoriasis-like conditions 
↓FLG expression Relevant upregulated genes in the pre-treated psoriasis model involved in KT differentiation were DSC1, FLG, LOR, and K1 
Relevant downregulated immune response genes were IL-1β and IL-20, which are both found to be highly upregulated in skin lesions of psoriasis patients 
Morin et al. [65] (2019) FTSE Self-assembly method Psoriatic HFs and KTs To characterize the psoriatic skin substitutes’ metabolism of tazarotene Irregular and scaly aspect and a thicker and less organized epidermis Almost 1% of the dose was metabolized as tazarotenic acid in both conditions 
Disorganized or even absent SC 
IVL expression throughout the epidermis 
↓ FLG expression 
↑ K14 expression 
Rioux et al. [66] (2018) FTSE Self-assembly method Psoriatic HFs and KTs To compare the pattern of genes expressed in a model of human psoriatic lesional skin with that of healthy and non-lesional skin substitutes Non-lesional skin substitutes → ↑epidermis than healthy substitutes Key players in the lipid metabolism of the SC and skin in general are repressed in the lesional psoriatic substitutes 
LCE gene family in lesional compared to non-lesional substitutes 
Models: healthy, lesional, and non-lesional Lesional skin substitutes → ↑epidermis than the healthy skin substitutes and showed a more disorganized structure The most deregulated pathways in the healthy against the lesional condition include keratinization, isoprenoid metabolic process, and retinoid metabolic process 
Desmet et al. [50] (2017) FTSE Commercial psoriatic skin model IL-1α, IL-6, IL-17A, and TNF-α To evaluate the therapeutic efficacy of liposome-encapsulated RNAi molecules suppressing genes encoding key players (IL-22RA1, K17, hBD-2, and TSLP) in psoriasis Not described Single siRNA treatments against K17, TSLP or DEFB4 were found to exert silencing effects 
↓Protein expression of K17, TSLP, or hBD-2 compared to untreated controls 
Treatment of the reconstructed skin model with the siRNA mix ↓IVL expression level and altered the expression of elafin significantly compared to untreated controls 
Ma et al. [51] (2017) RHE Immature commercial epidermal skin substitutes IL-17A, IL-22, TNF-α To synthese a novel molecule, bakuchiol salicylate (bakusylan), with a modulatory gene expression profile similar to retinoids Not described Only bakusylan, compared with three current prescription retinoids, favorably modulated three important genes dysregulated by psoriasiform cytokines: STAT3, IL-8, and CXCL3 
Niehues et al. [54] (2017) RHE Primary NHEKs for epidermis development Th1 or Th17 T cells combinations of cytokines To perform quantitative trait locus analysis, utilizing RNA-seq data from human skin and confirm the findings in a 3D skin model Not described Th1 cytokines induced expression of all tested LCE family genes, whereas Th17 cytokines increased LCE2 and LCE3 genes 
LCE3B/C-deletion is not associated with altered skin barrier function. LCE3A appeared to be the strongest antimicrobial protein of the tested LCEs 
Pfaff et al. [52] (2017) FTSE Collagen-based method IL-17A To address the role of IL-17A in KT differentiation IL-17A disturbs KT differentiation in FTSE 
↓Genes encoding differentiation-associated proteins, chemokines, cytokines, and AMPs 
↑Genes encoding AMPs and IL-36 family members 
↑Psoriasin, Calgranulin-A, Calgranulin-B, koebnerisin, and hBD-2 
IL-17A activates the antimicrobial barrier of the skin 
Smits et al. [48] (2017) RHE Immortalized KT cell lines N/TERT1 or N/TERT2G for epidermis development Th1 cytokines (TNF-α, IL-6, and IL-1α) or Th17 cytokines (IL-17 and IL-22) To compare N/TERT1, N/TERT2G cell lines to primary NHEKs based on epidermal differentiation, response to inflammatory mediators, and the development of normal and inflammatory human epidermal equivalents Parakeratosis, thickening of the SC, and the absence of a stratum granulosum 
↓FLG and LOR + ↑IVL expression 
↑Psoriasis-related host defense genes PI3 and DEFB4 
Depieri et al. [57] (2016) FTSE Commercial psoriatic skin model Non-additional induction To study the potential use of liquid crystalline nanodispersion as a siRNA delivery system to reduce the IL-6 levels in a psoriasis skin model Not described A single treatment with IL-6 siRNA for 6 h was able to reduce the extracellular IL-6 levels by 3.3-fold compared with control 
Duque-Fernández et al. [72] (2016) FTSE Self-assembly method Psoriatic patients To compare the impact of using SFM instead of complete culture medium during the last step of psoriatic skin substitute reconstruction Disorganized epidermis Serum-free culture conditions did not seem to have a strong impact on the macroscopic aspect and histologic features of both kinds of substitutes 
↓FLG expression 
Models: HSE+serum, HSE-serum, PSE+serum, PSE-serum ↑IVL expression Psoriatic skin substitutes did not appear to be affected by a serum-free culture in regards to their lipid chain order 
KT hyperproliferation 
Disorganized lipidic system 
Harvey et al. [56] (2016) FTSE Commercial psoriatic skin model IL-22 To examine the effects of the IL-22 treatment the structure of the psoriatic model and to observe the spatial location of the psoriatic therapy drug acetretin Acanthosis, abnormalities in epidermal differentiation After 24 h, acetretin was primarily located in the epidermal regions of both the psoriatic and non psoriatic models whereas after 48 h it was detectable in the dermis 
↑Epidermal thickness 
↑Psoriasin expression 
Henry et al. [47] (2016) FTSE Collagen-based method IL-36 To explore the biological effects of active IL-36 in a FTSE model Cathepsin G-processed IL-36β was sufficient to perturb skin differentiation with significant epidermal thickening and expanded stratum layers 
Pouliot-Bérubé et al. [71] (2016) FTSE Self-assembly method TNF-α, IL-1α IL-17a, and IL-6 To evaluate whether the addition of a cytokine cocktail (IL-1α, IL-6, IL-17A, and TNF-α) could compensate for the lack of immune cells in the reconstructed psoriatic skin model Disorganized epidermis, significant cell growth, and thicker dermis The most positively influenced pathways in the reconstructed psoriatic skin grown with cytokines include inflammatory response, defense response and cell chemotaxis among others 
Downregulated pathways include KT differentiation, epidermal cell differentiation, skin development and establishment of skin barrier 
Chamcheu et al. (2015) [70FTSE Commercial psoriatic skin model Non additional induction To investigate the effect of DEL on psoriatic epidermal KT differentiation, proliferation and inflammation using a 3D-human psoriatic skin model Not described ↑Cornification associated with epidermal thinning, and ↑ in the mRNA and protein expression of markers of differentiation 
↑ caspase-14 and FLG 
↓ Expression of markers of proliferation and inflammation 
Dose-dependently suppresses the expression of psoriasin and koebnerisin 
↓The increased release of KT-associated pro-inflammatory cytokines 
Jean et al. [69] (2015) FTSE Self-assembly method Psoriatic HFs and KTs To develop and characterize a reproducible invitro psoriatic skin model produced with involved or uninvolved cells, in order to reach a better understanding of the differences between these psoriatic skins. The ultimate goal is to elucidate the triggering factor responsible for psoriatic plaque formation Involved substitutes 
Three different kinds of skin substitutes ↑ Living epidermis and a poor cohesion of the SC 
1. Normal substitutes: normal HFs and KTs ↑ Cell proliferation, p63 expression and permeability to hydrocortisone compared with normal substitutes 
2. Uninvolved substitutes: uninvolved psoriatic HFs and KTs Uninvolved profile 1 
3. Involved substitutes: involved psoriatic HFs and KTs A thin, well-differentiated epidermis, such as observed in normal substitutes. Cell proliferation, p63 expression and impermeability similar to normal substitutes 
They were classified in two profiles Uninvolved profile 2 
Profile 1 was associated with uninvolved substitutes, which had characteristics similar to normal substitutes; and profile 2, to uninvolved substitutes rather mimicking the involved skin ↑ Living epidermis similar to involved substitute epidermis 
Cell proliferation, p63 expression and poor impermeability similar to involved substitutes 
Ayata et al. [67] (2014) FTSE Self-assembly method Psoriatic patients To construct an in vitro vascularized psoriatic skin substitute for fundamental research Rough epidermal structure and ↑epidermal thickness ECs organized and rebuilt the tube-like structures in which lumen exists surrounded by ECs. ECs kept their characteristic features during skin reconstruction 
ECs were seeded onto the fibroblast sheets and cultivated for an additional week Presence of tip cells, which are specialized ECs that promote and guide the capillaries sprouting via their filopodia 
Van den Bogaard et al. [53] (2012) FTSE DED Cytokine mix (IL-1α, TNF-α, and IL-6) To evaluate the effects of Y-27632 on PSE development After cytokine stimulation, the protein expression of the psoriatic markers hBD-2 and SKALP/elafin was strongly induced, indicating that PSEs can be generated from Y-27632-treated KTs 
Y-27632 was supplemented in the culture medium at indicated culture periods and concentrations 
Jean et al. [68] (2011) FTSE Self-assembly method Psoriatic patients To compare the development of psoriatic substitutes cultured in a retinoic acid supplemented medium with those cultured in medium receiving no supplement, to define the effects of this growth factor on KT proliferation and differentiation ↑Epidermal thickness PSE cultured with retinoic acid have a thinner epidermis 
↑K5 and 14 expression 
↑K6 and 16 expression in the suprabasal layers When PSEs were treated with retinoic acid, the expression of K10, transglutaminase, IVL, FLG, and LOR was restored 
↓K10, LOR, and FLG expression 
↑Transglutaminase and IVL. 
Krajewska et al. [43] (2010) FTSE DED Putrescine To further develop this in vitro model by introducing ECs to mimic the increased vascularization found in psoriasis Immature KTs present throughout the epidermal layer, with the majority of layers retaining nuclei When the KT-conditioned medium is added to HFs, a small percentage of primary stem cells present in these cultures are activated to differentiate to CD133+, CD34+, and CD31+ cells. The addition of putrescine to KTs stimulates this process 
HDMECs were co-seeded with HFs 
Authors and publication dateIn vitro modelCompositionObjectivePsoriasis hallmarksOutcomes
methodpsoriasis induction
Martínez-Morcillo et al. [25] (2021) RHE Primary NHEKs for epidermis development Th17 cytokines IL-17A and IL-22 To investigate the role played by NAD+ and PAR metabolism in skin oxidative stress and inflammation Not described ↑NAMPT transcript levels in psoriatic epidermis 
Pharmacological inhibition of NADPH oxidases with apocynin ↓the mRNA levels of DEFB4, while it did not affect FLG and LOR
Inhibition of NAMPT, PARP, and AIFM1 reduced the transcript levels DEFB4 and S100A8 
Simard et al. [61] (2021) FTSE Self-assembly method Psoriatic HFs and KTs To investigate the effects of ALA on the proliferation and differentiation ↑Epidermal thickness and higher levels of proliferative KTs ↓KT proliferation 
↑Psoriatic substitute epidermal differentiation (↓ FLG and LOR) 
Models: HSE, HSE+ALA, PSE, PSE+ALA ALA was incorporated into the epidermal phospholipids and metabolized into long-chain n-3 polyunsaturated fatty acids 
The kinases 1 and 2 were the most activated after ALA supplementation 
Cardinali et al. [55] (2021) RHE The immortalized human KT cell line Ker-CT was used to generate epidermis Th1/Th17 cytokines, TNF-α, IL-6, IL-1α, and IL-17A To test the safety profile and the biological activity of NPD-0614-13 and NPD-0614-24, two AhR ligands structurally related to FICZ, known to be effective in psoriasis Thickening of the SC and the loss of the granular layer Both ↑epidermal morphology and ↓the SC thickness in psoriatic RHEs 
↓IVL and FLG expressions ↓Psoriasin, hBD-2 and the mRNA expression of all pro-inflammatory cytokines 
FTSE NHEKs and psoriatic HFs harvested from psoriasis lesions. No description of the method Psoriatic HFs ↑ S100A7, hBD-2 and psoriasin expressions The treatment of a 3D psoriatic FTSE with both compounds ↑ the differentiation process (↑SC thickening and expression of FLG) 
Treatment ↓ expression of hBD-2 and the release of pro-inflammatory cytokines IL-6 and IL-8 
Ampawong et al. [28] (2020) FTSE Collagen-based method Psoriatic KTs To evaluate the role of black-colored rice crude extract in alleviating the symptoms of psoriasis ↑Epidermal thickness, acanthosis, hyperkeratosis, and epidermal inflammation ↓Epidermal thickness and 3-caspase, psoriasin, and koebnerisin expression levels 
↑Psoriasin and koebnerisin expressions ↑Antioxidant capacity (Nfr2 expression) 
↑Pro-inflammatory cytokines ↑Caspase-14, FLG and IVL expression 
↓Pro-inflammatory cytokines and ↑IL-4 and TGF-β 
Simard et al. [62] (2020) FTSE Self-assembly method Psoriatic HFs and KTs To evaluate the impact of either CT or ISO on the pathological characteristics of the dermatosis while producing a psoriatic skin model Not described PSE+CT and PSE+ISO → ↑epidermal proliferation 
The hyperproliferation was greater in the epidermis of PSE+CT than PSE+ISO. 
↓FLG, K10, and cAMP ↑IVL in PSE+CT. 
Models: HSE+CT, HSE+ISO, PSE+CT, PSE+ISO. ADCY genes in PSE+CT than in HSE+CT. 
↓ADRB2 was decreased in PSE+CT. 
↑AC9 levels in psoriatic substitutes 
Shin et al. [58] (2020) FTSE Collagen-based method Activated T cells To recapitulate inflammatory skin diseases using patient-specific cells and a physiological in vitro platform that allows for dissecting epidermal and immune cell interactions as well as quantification of T cell migration into the skin in the context of disease progression and drug treatment T cells migrated into the dermis and retained their proliferative state 
Models Th1/Th17-bearing pFTSEs exhibited a ↑expression of K16, a ↓expression of PPP6c, and ↑epidermis, resembling the psoriatic epidermal phenotype and produced ↑concentrations of pro-inflammatory cytokines 
Th1/Th17-bearing psoriatic FTSE (in vitro polarized) CCR6+CLA+ T cell-bearing pFTSEs showed ↑K16 and hBD-2, and ↓PPP6c representing the psoriatic epidermal phenotype 
CCR6+CLA+ T cell-bearing psoriatic FTSE (psoriatic patient T cells) Treatment with neutralizing anti-IL-17A antibodies reversed these markers 
CCR6CLA- T cell-bearing psoriatic FTSE. 
Bélanger et al. [63] (2019) FTSE Self-assembly method Psoriatic HFs and KTs To investigate the antipsoriatic activities of dihydrochalcone derivatives from Populus balsamifera L.buds, known as balsacones ↑Epidermal thickness Standard treatment MTX or balsacones show a significant ↓in the thickness of the living epidermis and IVL and LOR expression seems partially or fully restored, suggesting a normalization of the differentiation process 
Hyperproliferation 
↑IVL expression All have anti-inflammatory and antioxidant potentials 
↓LOR expression 
Chamcheu, JC et al. (2019) [46FTSE Collagen-based method Activated T cells To characterize the effects of fisetin in a 3D psoriasis-like disease model ↑ Epidermal thickness and proliferation Topical application of fisetin modulates psoriasis-like features, suppresses proliferation and mTOR activation and inflammation, and modulates differentiation 
Aberrant expression of differentiation markers 
↑ Psoriasin and IL-17A secretion 
Lorthois et al. [64] (2019) FTSE Self-assembly method Activated T cells To develop and analyze the effect of activated T cells in lesional reconstructed skin models, compared to T cell-free healthy and lesional skin models, to evaluate the impact of T cells on the lesional skin phenotype and on psoriatic key markers At day 21, most lymphocytes migrated within the dermal compartment, while few of them migrated to the epidermis, closely mimicking the in vivo infiltration of T cells in lesional plaques 
The infiltration of activated T cells significantly dramatically increased the thickness of LS at day 21 
Models: HSE, LS, LS+T The addition of T cells ↑the proliferation within the dermal compartment of lesional skin models 
Lesional immunocompetent skin models promoted sustained and chronic inflammation induced by T cells 
T cells are partly responsible for the activation of the STAT1 pathway 
Clarysse et al. [59] (2019) FTSE Collagen-based method IL-17A, IL-22, and TNF-α To address the direct impact of kinase inhibition of the JAK1/3 pathways by tofacitinib on KT immune function and barrier formation in psoriasis Hyperkeratosis, parakeratosis and acantosis Psoriasis-like morphologic features were prevented by tofacitinib compared to sham-treated conditions 
FLG expression was mild preserved by tofacitinib in psoriasis-like conditions 
↓FLG expression Relevant upregulated genes in the pre-treated psoriasis model involved in KT differentiation were DSC1, FLG, LOR, and K1 
Relevant downregulated immune response genes were IL-1β and IL-20, which are both found to be highly upregulated in skin lesions of psoriasis patients 
Morin et al. [65] (2019) FTSE Self-assembly method Psoriatic HFs and KTs To characterize the psoriatic skin substitutes’ metabolism of tazarotene Irregular and scaly aspect and a thicker and less organized epidermis Almost 1% of the dose was metabolized as tazarotenic acid in both conditions 
Disorganized or even absent SC 
IVL expression throughout the epidermis 
↓ FLG expression 
↑ K14 expression 
Rioux et al. [66] (2018) FTSE Self-assembly method Psoriatic HFs and KTs To compare the pattern of genes expressed in a model of human psoriatic lesional skin with that of healthy and non-lesional skin substitutes Non-lesional skin substitutes → ↑epidermis than healthy substitutes Key players in the lipid metabolism of the SC and skin in general are repressed in the lesional psoriatic substitutes 
LCE gene family in lesional compared to non-lesional substitutes 
Models: healthy, lesional, and non-lesional Lesional skin substitutes → ↑epidermis than the healthy skin substitutes and showed a more disorganized structure The most deregulated pathways in the healthy against the lesional condition include keratinization, isoprenoid metabolic process, and retinoid metabolic process 
Desmet et al. [50] (2017) FTSE Commercial psoriatic skin model IL-1α, IL-6, IL-17A, and TNF-α To evaluate the therapeutic efficacy of liposome-encapsulated RNAi molecules suppressing genes encoding key players (IL-22RA1, K17, hBD-2, and TSLP) in psoriasis Not described Single siRNA treatments against K17, TSLP or DEFB4 were found to exert silencing effects 
↓Protein expression of K17, TSLP, or hBD-2 compared to untreated controls 
Treatment of the reconstructed skin model with the siRNA mix ↓IVL expression level and altered the expression of elafin significantly compared to untreated controls 
Ma et al. [51] (2017) RHE Immature commercial epidermal skin substitutes IL-17A, IL-22, TNF-α To synthese a novel molecule, bakuchiol salicylate (bakusylan), with a modulatory gene expression profile similar to retinoids Not described Only bakusylan, compared with three current prescription retinoids, favorably modulated three important genes dysregulated by psoriasiform cytokines: STAT3, IL-8, and CXCL3 
Niehues et al. [54] (2017) RHE Primary NHEKs for epidermis development Th1 or Th17 T cells combinations of cytokines To perform quantitative trait locus analysis, utilizing RNA-seq data from human skin and confirm the findings in a 3D skin model Not described Th1 cytokines induced expression of all tested LCE family genes, whereas Th17 cytokines increased LCE2 and LCE3 genes 
LCE3B/C-deletion is not associated with altered skin barrier function. LCE3A appeared to be the strongest antimicrobial protein of the tested LCEs 
Pfaff et al. [52] (2017) FTSE Collagen-based method IL-17A To address the role of IL-17A in KT differentiation IL-17A disturbs KT differentiation in FTSE 
↓Genes encoding differentiation-associated proteins, chemokines, cytokines, and AMPs 
↑Genes encoding AMPs and IL-36 family members 
↑Psoriasin, Calgranulin-A, Calgranulin-B, koebnerisin, and hBD-2 
IL-17A activates the antimicrobial barrier of the skin 
Smits et al. [48] (2017) RHE Immortalized KT cell lines N/TERT1 or N/TERT2G for epidermis development Th1 cytokines (TNF-α, IL-6, and IL-1α) or Th17 cytokines (IL-17 and IL-22) To compare N/TERT1, N/TERT2G cell lines to primary NHEKs based on epidermal differentiation, response to inflammatory mediators, and the development of normal and inflammatory human epidermal equivalents Parakeratosis, thickening of the SC, and the absence of a stratum granulosum 
↓FLG and LOR + ↑IVL expression 
↑Psoriasis-related host defense genes PI3 and DEFB4 
Depieri et al. [57] (2016) FTSE Commercial psoriatic skin model Non-additional induction To study the potential use of liquid crystalline nanodispersion as a siRNA delivery system to reduce the IL-6 levels in a psoriasis skin model Not described A single treatment with IL-6 siRNA for 6 h was able to reduce the extracellular IL-6 levels by 3.3-fold compared with control 
Duque-Fernández et al. [72] (2016) FTSE Self-assembly method Psoriatic patients To compare the impact of using SFM instead of complete culture medium during the last step of psoriatic skin substitute reconstruction Disorganized epidermis Serum-free culture conditions did not seem to have a strong impact on the macroscopic aspect and histologic features of both kinds of substitutes 
↓FLG expression 
Models: HSE+serum, HSE-serum, PSE+serum, PSE-serum ↑IVL expression Psoriatic skin substitutes did not appear to be affected by a serum-free culture in regards to their lipid chain order 
KT hyperproliferation 
Disorganized lipidic system 
Harvey et al. [56] (2016) FTSE Commercial psoriatic skin model IL-22 To examine the effects of the IL-22 treatment the structure of the psoriatic model and to observe the spatial location of the psoriatic therapy drug acetretin Acanthosis, abnormalities in epidermal differentiation After 24 h, acetretin was primarily located in the epidermal regions of both the psoriatic and non psoriatic models whereas after 48 h it was detectable in the dermis 
↑Epidermal thickness 
↑Psoriasin expression 
Henry et al. [47] (2016) FTSE Collagen-based method IL-36 To explore the biological effects of active IL-36 in a FTSE model Cathepsin G-processed IL-36β was sufficient to perturb skin differentiation with significant epidermal thickening and expanded stratum layers 
Pouliot-Bérubé et al. [71] (2016) FTSE Self-assembly method TNF-α, IL-1α IL-17a, and IL-6 To evaluate whether the addition of a cytokine cocktail (IL-1α, IL-6, IL-17A, and TNF-α) could compensate for the lack of immune cells in the reconstructed psoriatic skin model Disorganized epidermis, significant cell growth, and thicker dermis The most positively influenced pathways in the reconstructed psoriatic skin grown with cytokines include inflammatory response, defense response and cell chemotaxis among others 
Downregulated pathways include KT differentiation, epidermal cell differentiation, skin development and establishment of skin barrier 
Chamcheu et al. (2015) [70FTSE Commercial psoriatic skin model Non additional induction To investigate the effect of DEL on psoriatic epidermal KT differentiation, proliferation and inflammation using a 3D-human psoriatic skin model Not described ↑Cornification associated with epidermal thinning, and ↑ in the mRNA and protein expression of markers of differentiation 
↑ caspase-14 and FLG 
↓ Expression of markers of proliferation and inflammation 
Dose-dependently suppresses the expression of psoriasin and koebnerisin 
↓The increased release of KT-associated pro-inflammatory cytokines 
Jean et al. [69] (2015) FTSE Self-assembly method Psoriatic HFs and KTs To develop and characterize a reproducible invitro psoriatic skin model produced with involved or uninvolved cells, in order to reach a better understanding of the differences between these psoriatic skins. The ultimate goal is to elucidate the triggering factor responsible for psoriatic plaque formation Involved substitutes 
Three different kinds of skin substitutes ↑ Living epidermis and a poor cohesion of the SC 
1. Normal substitutes: normal HFs and KTs ↑ Cell proliferation, p63 expression and permeability to hydrocortisone compared with normal substitutes 
2. Uninvolved substitutes: uninvolved psoriatic HFs and KTs Uninvolved profile 1 
3. Involved substitutes: involved psoriatic HFs and KTs A thin, well-differentiated epidermis, such as observed in normal substitutes. Cell proliferation, p63 expression and impermeability similar to normal substitutes 
They were classified in two profiles Uninvolved profile 2 
Profile 1 was associated with uninvolved substitutes, which had characteristics similar to normal substitutes; and profile 2, to uninvolved substitutes rather mimicking the involved skin ↑ Living epidermis similar to involved substitute epidermis 
Cell proliferation, p63 expression and poor impermeability similar to involved substitutes 
Ayata et al. [67] (2014) FTSE Self-assembly method Psoriatic patients To construct an in vitro vascularized psoriatic skin substitute for fundamental research Rough epidermal structure and ↑epidermal thickness ECs organized and rebuilt the tube-like structures in which lumen exists surrounded by ECs. ECs kept their characteristic features during skin reconstruction 
ECs were seeded onto the fibroblast sheets and cultivated for an additional week Presence of tip cells, which are specialized ECs that promote and guide the capillaries sprouting via their filopodia 
Van den Bogaard et al. [53] (2012) FTSE DED Cytokine mix (IL-1α, TNF-α, and IL-6) To evaluate the effects of Y-27632 on PSE development After cytokine stimulation, the protein expression of the psoriatic markers hBD-2 and SKALP/elafin was strongly induced, indicating that PSEs can be generated from Y-27632-treated KTs 
Y-27632 was supplemented in the culture medium at indicated culture periods and concentrations 
Jean et al. [68] (2011) FTSE Self-assembly method Psoriatic patients To compare the development of psoriatic substitutes cultured in a retinoic acid supplemented medium with those cultured in medium receiving no supplement, to define the effects of this growth factor on KT proliferation and differentiation ↑Epidermal thickness PSE cultured with retinoic acid have a thinner epidermis 
↑K5 and 14 expression 
↑K6 and 16 expression in the suprabasal layers When PSEs were treated with retinoic acid, the expression of K10, transglutaminase, IVL, FLG, and LOR was restored 
↓K10, LOR, and FLG expression 
↑Transglutaminase and IVL. 
Krajewska et al. [43] (2010) FTSE DED Putrescine To further develop this in vitro model by introducing ECs to mimic the increased vascularization found in psoriasis Immature KTs present throughout the epidermal layer, with the majority of layers retaining nuclei When the KT-conditioned medium is added to HFs, a small percentage of primary stem cells present in these cultures are activated to differentiate to CD133+, CD34+, and CD31+ cells. The addition of putrescine to KTs stimulates this process 
HDMECs were co-seeded with HFs 

AC9, adenylate cyclase type 9; ADCY, adenylyl cyclase; ADRB2, adrenoceptor β2; AhR, ary hydrocarbon receptor; ALA, α-linolenic acid; AMPs, antimicrobial peptides; cAMP, cyclic adenosine monophosphate; CT, cholera toxin; CXCL, chemokines; DED, de-epidermized dermis; DEFB4 β, defensin 4; DEL, delphinidin; DSC1, desmocollin 1; ECs, endothelial cells; FICZ, formylindolo[3,2-b] carbazole; FLG, filaggrin; FTSE, full-thickness skin equivalent; hBD-2, human β-defensin-2; HDMECs, human dermal microvascular endothelial cells; HFs, human fibroblasts; HSE, human skin equivalent; IL, interleukin; ISO, isoproterenol; IVL, involucrin; JAK1/3, Janus Kinase 1 and 3,K Keratin; KTs, keratinocytes; LCE, late cornified envelope; LS, lesional skin; LOR, loricrin; MTX, methotrexate; mTOR, mammalian target of rapamycin; NAD+, nicotinamide adenine dinucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NHEK, normal human epidermal keratinocytes; Nrf-2, nuclear factor erythroid 2-related factor 2; PAR, poly(ADP)-ribosylation; PPP6c, serine/threonine-protein phosphatase 6 catalytic subunit; PSE, psoriatic skin equivalent; RHE, reconstructed human epidermal equivalent; SC, stratum corneum; SKALP, skin-derived anti-leukoproteinase; STAT1, signal transducer and activator of transcription 1 gene; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α; TSLP, thymic stromal lymphopoietin.

For instance, regarding RHE, Martinez-Morcillo et al. [25] investigated the role played by NAD+ and poly (ADP)-ribosylation (PAR) metabolism in skin oxidative stress and inflammation. They found that inhibition of nicotinamide phosphoribosyltransferase, PARP, and apoptosis-inducing factor mitochondria associated 1 (AIFM1) reduced the transcript levels DEFB4 and S100A8, inflammation markers associated with psoriasis. Another finding based on the use of RHE is the testing of the safety profile and the biological activity of NPD-0614-13 and NPD-0614-24, two new synthetic AhRAry hydrocarbon receptor ligands structurally related to the natural agonist formylindole[3,2-b] carbazole (FICZ), known to be effective in psoriasis [55]. Furthermore, Ma, et al. [51] found that bakusylan, a novel molecule, favorably modulated three important genes dysregulated by psoriasiform cytokines using RHE.

However, most research in this field uses FTSE as a model of psoriasis. In this way, Simard et al. [61] induced psoriasis in a self-assembly based FTSE to investigate the effects of α-linolenic acid on the proliferation and differentiation of psoriatic KTs. They found a reduction in KT proliferation and an improvement in the psoriatic epidermal differentiation. Ampawong et al. [28] evaluated the role of black-colored rice crude extract in alleviating the symptoms of psoriasis in a collagen-based FTSE and reported a reduction of epidermal thickness, 3-caspase, psoriasin, and koebnerisin expression levels and secretion of pro-inflammatory cytokines. They also found an increment in antioxidant capacity and caspase-14, FLG and involucrin expression. Regarding DED-based FTSE, Van den Bogaard et al. [53] evaluated the effects of Y-27632 on human skin equivalent development and found that after being added during the submerged phase and inducing psoriasis by cytokine stimulation, this pharmacological inhibitor strongly induced the protein expression of the psoriatic markers human β-defensin 2 and skin-derived anti-leukoproteinase/elafin.

Interestingly, other types of cells can be used to develop 3D models in addition to HFs and KTs. For example, Shin et al. [58] developed an immunocompetent collagen-based FTSE incorporating in vitro polarized Th1/Th17 cells or CCR6+CLA+ T cells derived from psoriasis patients into the constructs in order to establish an in vitro platform for dissecting epidermal and immune cell interactions as well as quantifying T-cell migration into the skin in the context of disease progression and drug treatment. Among their findings, they reported that both immunocompetent models exhibited a psoriatic epidermal phenotype. In addition, Ayata et al. [67] added endothelial cells (ECs) to their psoriatic FTSE to construct an in vitro vascularized psoriatic skin substitute for fundamental research. In this line, Krajewska et al. [43] also added ECs to their psoriatic FTSE. In this case, the objective was to mimic the increased vascularization found in psoriasis. Finally, regarding commercial FTSE, Desmet et al. [50] evaluated the therapeutic efficacy of liposome-encapsulated RNAi molecules suppressing genes encoding key players in psoriasis in various psoriatic in vitro models and Chamcheu et al. [70] investigated the effect of DEL on psoriatic epidermal KT differentiation, proliferation, and inflammation.

Ex vivo Models

Ex vivo models of psoriasis are developed from human skin explants excised from healthy donors [73‒75] and animal skins mainly obtained from mice and pigs [27]. Therefore, they conserved skin complexity including a fully competent skin barrier and presence and/or diversity of immune cells.

Different approaches have been developed in order to mimic psoriasis in ex vivo models. One of them is to achieve disruption of the skin barrier through treatment with serine proteases such as trypsin and plasmin [73, 74]. This approach resulted in increased transepidermal water loss, alteration of skin barrier proteins such as corneodesmosin, occludin, and zonula occludens-1 and increased expression of inflammatory markers like IL-6, IL-8, and thymic stromal lymphopoietin. SC stripping is another strategy for disrupting the skin barrier. Lee W R et al. used this along with de-lipid, de-sebum and de-protein of mouse and pig skins to examine the flux of small interfering RNA across those skins after laser treatment, and reported a 33- and 14-fold enhancement of this flux [27].

In addition to the disruption of the skin barrier, some authors have included the incorporation and/or activation of T cells in their ex vivo models. For instance, Rancan et al. [73] cocultured their human skin explants with Jurkat T cells and activated them with phytohemagglutinin, IL-17A, and IL-22 in order to test redox-sensitive core multishell-nanocarriers loaded with rapamycin. They reported the alteration of skin barrier proteins but failed to detect inflammatory markers of psoriasis. In this line, Jardet et al. [75] in situ activated and sustained the polarization of skin-resident Th17 cells reporting psoriasis hallmarks such as a loss of viability and structural integrity of the epidermis and increased expression of S100A7 and K16 in the suprabasal layers of the epidermis, among others (Table 4).

Table 4.

Ex vivo models of psoriasis disease

Authors and publication dateEx vivo modelPsoriasis inductionObjectivePsoriasis hallmarksOutcomes
Rancan et al. [73] (2021) Human skin explants co-cultured with Jurkat T cells Trypsin + PHA, IL-17A, and IL-22 To test redox-sensitive CMS-NC loaded with rapamycin using an inflammatory skin model Alteration of skin barrier proteins CDSN, Occl and ZO-1 Rapamycin formulations exerted inhibitory effects on T cells 
No effects on skin inflammatory markers were detected Better drug delivery of the oxidative-sensitive CMS-NC over the other formulations 
Frombach et al. [74] (2020) Human skin explants Trypsin and plasmin (SPs) treatment To assess the penetration and biological effects of the anti-inflammatory drug DXM, encapsulated in CMS-NC, when compared to a standard cream formulation The rates of TEWL increased to about 2.5-fold of the initial value ↓Inflammatory response after topical application of DXM formulations 
↑Expression of IL-6, IL-8, and TSLP after 40 h incubation with SP. The drug concentrations in the tissue extracts revealed a marked increase of drug in SP-treated compared to untreated skin 
Jardet et al. [75] (2020) Human skin explants In situ activation of skin-resident Th17 cells by intradermal injection of anti-CD3 and anti-CD28 antibodies To develop a novel human Th17-driven skin inflammation model based on in situ activation of skin-resident Th17 cells Loss of viability and structure integrity of the epidermis In situ T-cell activation was sufficient to activate both Th17 and Th1 cells 
↑Expression of S100A7 and K16 in the suprabasal layers of the epidermis 
Th17 cell polarization is sustained by culture in a chemically defined medium supplemented with IL-1β, IL-23 and TGF-β for 7 days LOR was absent The presence of the Th17 polarization cocktail allowed a more pronounced expression of all pro-inflammatory cytokines 
   IVL was found in the suprabasal layers of the epidermis in the inflammatory model 
Lee et al. [27] (2020) Nude mouse and pig skins SC stripping + de-lipid, de-sebum and de-protein of the skins To examine the flux of siRNA across nude mouse and pig skins with pretreatment of SC stripping and removal of lipid, sebum, or protein after laser treatment Not described The laser treatment resulted in the enhancement of siRNA flux by 33- and 14-fold as compared to the control 
Authors and publication dateEx vivo modelPsoriasis inductionObjectivePsoriasis hallmarksOutcomes
Rancan et al. [73] (2021) Human skin explants co-cultured with Jurkat T cells Trypsin + PHA, IL-17A, and IL-22 To test redox-sensitive CMS-NC loaded with rapamycin using an inflammatory skin model Alteration of skin barrier proteins CDSN, Occl and ZO-1 Rapamycin formulations exerted inhibitory effects on T cells 
No effects on skin inflammatory markers were detected Better drug delivery of the oxidative-sensitive CMS-NC over the other formulations 
Frombach et al. [74] (2020) Human skin explants Trypsin and plasmin (SPs) treatment To assess the penetration and biological effects of the anti-inflammatory drug DXM, encapsulated in CMS-NC, when compared to a standard cream formulation The rates of TEWL increased to about 2.5-fold of the initial value ↓Inflammatory response after topical application of DXM formulations 
↑Expression of IL-6, IL-8, and TSLP after 40 h incubation with SP. The drug concentrations in the tissue extracts revealed a marked increase of drug in SP-treated compared to untreated skin 
Jardet et al. [75] (2020) Human skin explants In situ activation of skin-resident Th17 cells by intradermal injection of anti-CD3 and anti-CD28 antibodies To develop a novel human Th17-driven skin inflammation model based on in situ activation of skin-resident Th17 cells Loss of viability and structure integrity of the epidermis In situ T-cell activation was sufficient to activate both Th17 and Th1 cells 
↑Expression of S100A7 and K16 in the suprabasal layers of the epidermis 
Th17 cell polarization is sustained by culture in a chemically defined medium supplemented with IL-1β, IL-23 and TGF-β for 7 days LOR was absent The presence of the Th17 polarization cocktail allowed a more pronounced expression of all pro-inflammatory cytokines 
   IVL was found in the suprabasal layers of the epidermis in the inflammatory model 
Lee et al. [27] (2020) Nude mouse and pig skins SC stripping + de-lipid, de-sebum and de-protein of the skins To examine the flux of siRNA across nude mouse and pig skins with pretreatment of SC stripping and removal of lipid, sebum, or protein after laser treatment Not described The laser treatment resulted in the enhancement of siRNA flux by 33- and 14-fold as compared to the control 

CDSN, corneodesmosin; CMS-NC, core multishell-nanocarriers; DXM, dexamethasone; IL, interleukin; K, keratin; IVL, involucrin; Occ1, occludin; LOR, loricrin; PHA, phytohemagglutinin; SC, stratum corneum; SPs, serin proteases; TEWL, transepidermal water loss; TGF-β, transforming growth factor β; TSLP, thymic stromal lymphopoietin; ZO-1, zonula occludens-1.

The ideal preclinical model for testing drugs for psoriasis should mimic all features of the disease: clinical, histological, cellular, and molecular. Throughout this review, different in vivo, in vitro, and ex vivo models containing signs of psoriatic skin have been summarized (Fig. 3). Nevertheless, given the complexity of the pathogenesis of the disease, no single model can be expected to include all the pathogenic mechanisms and aspects that manifest in affected humans [10].

Fig. 3.

In vivo, in vitro, and ex vivo models of psoriasis. DED, de-epidermized dermis; FTSE, full-thickness skin equivalents; IL, interleukin; RHE, reconstructed human epidermal equivalent; PHA, phytohemagglutinin; TFG-β, transforming growth factor β. Created with biorender.com.

Fig. 3.

In vivo, in vitro, and ex vivo models of psoriasis. DED, de-epidermized dermis; FTSE, full-thickness skin equivalents; IL, interleukin; RHE, reconstructed human epidermal equivalent; PHA, phytohemagglutinin; TFG-β, transforming growth factor β. Created with biorender.com.

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In the case of using animal models, it is very important to bear in mind that for ethical reasons it should be possible to control the onset and severity of the disease in order not to compromise their health [10]. They have the advantage of showing the complexity of the whole organ and its interaction with other organs [13]. However, there are intrinsic differences between species that limit the clinical translation of the results obtained in previous research, leading to changes in safety and/or efficacy [19]. For example, the differences observed at the immunological level result in poor prediction of the human immune response, causing many of the tested drugs to fail during clinical trials [42]. This deficiency may be partially addressed by humanized mice, as immunodeficient mice are grafted with human immune cells, although they still have limitations. For instance, there are cytokines and other factors that are species-specific, such as IL-37 (involved in inflammation and barrier function), which is expressed in humans but not in mice [37].

Another obvious difference is that rodents’ bodies are covered with fur, whereas in humans the proportion of hair is much lower. This makes the mice’s skin much more permeable than that of humans. Such a limitation could be avoided by using nude mice whose skin would be much more similar to human skin in terms of percutaneous absorption [13]. Also, at the level of skin structure, mice have a thinner epidermis which contributes to a reduced barrier function resulting in increased absorption. This may be further altered after inducing the psoriatic phenotype, which would affect the absorption pattern of some therapeutic agents. Moreover, they have a muscular layer beneath the adipose tissue that is absent in humans [10]. This muscular layer is involved in the wound healing process by early contraction, whereas in humans wound closure occurs by proliferation and migration of KTs [13].

This difficulty in mimicking many human diseases in animal models, coupled with the need to study disease under controlled conditions, has given rise to an emerging field within tissue engineering focused on creating in vitro models [19]. As seen throughout this systematic review, in vitro models of psoriasis include 2D and 3D equivalents. 2D models are inexpensive and straightforward to maintain but cannot mimic skin structures and do not represent cell-to-cell or cell-to-ECM interactions in the 3D environment [49], which is important for the normal growth and function of cells. Furthermore, the absence of the 3D environment limits the testing of skin barrier function [76, 77]. The same issue is observed in RHE, which despite being a 3D equivalent and modeling the skin barrier, cannot be used to study the interactions between epidermis and dermis.

On the contrary, FTSE is composed of two or more layers and allow communication between different cell types, mimicking the in vivo situation more precisely [3]. However, not all FTSEs have the same properties, as those properties are influenced by the way they are created. For instance, collagen-based FTSE are easily and quickly produced but they have shown high contraction and instability issues [77]. DED-based FTSE often lack HFs in the dermal component, which is not representative of native skin [77]. FTSE developed through the self-assembly method more closely represent either normal or pathogenic skin for in vitro studies because of the absence of synthetic biomaterials and the fully autologous source of cells, but their efficacy depends on HFs capability to produce a sufficient amount of ECM [77].

Although they contain a stratified epidermis, FTSE models lack a fully competent skin barrier and the exact cellular architecture and compartments, such as the different immune cell types, which are all present in human skin [75]. Ex vivo models, as they are obtained from human or animal explants, conserved skin complexity including a fully competent skin barrier and presence and/or diversity of immune cells. However, the limited availability of explants and the need for an invasive procedure to obtain them are important limitations of these ex vivo models.

Regardless of the method used to construct these in vitro 3D models, they are all time-consuming and labor-intensive, as they use various types of primary cells and depend on the proficiency of researchers and sources of cells [49]. It is extremely difficult to completely capture the degree of complexity of psoriasis with primary cells, due to their limited availability and/or growth potential [78]. In fact, because of these limitations, there are few studies where immune cells are integrated in the psoriasis model [46, 58, 64]. In this sense, induced pluripotent stem cells (iPSCs) could provide an unlimited supply of different cells representing different organs for healthy and diseased models from a single donor [42].

Other challenges in this field include reproducibility within other models, cost-effective ratio, and short shelf-life parameters [39]. Commercially available 3D psoriasis models may represent a valuable alternative to in-house developed systems and could provide more reproducible results [3, 39]. This model includes normal human-derived epidermal KTs and psoriatic dermal HFs, expressing psoriasis-specific markers and releasing psoriasis-specific pro-inflammatory cytokines [39]. They are fully validated and standardized. However, there are few studies [50, 51, 56, 57, 70] using them to research psoriasis, possibly because they are very expensive and have low shelf storage time [39]. Furthermore, immune cells are lacking in these commercial models [50]. Table 5 presents the advantages, limitations, and applications of in vivo, in vitro, and ex vivo models in more detail. Bearing in mind the philosophy of 3Rs, the decision of which model to use focuses on in vitro models. The choice will depend on the study hypothesis (Fig. 4) and a combination of different models that complement each other is recommended.

Table 5.

Advantages, limitations, and principal applications of in vivo, in vitro, and ex vivo models

ModelDetailedAdvantagesLimitationsPrincipal applications
In vivo 
 Generals All Zebrafish Human-like genome Ethical considerations Systematic detection of drugs by adding compounds to water 
Easy genetic manipulation Surrounding liquid environment 
Embryo transparency and rapid development with a high number of offspring Lack of epidermal barrier and appendages Study of the participation of certain compounds in chronic inflammation 
Less perception of pain and feeling of stress Presence of scales in adult fish 
Rodents Possibility of studying the interaction between cellular components Differences between strains of mice To determine the efficacy and safety of certain compounds or drugs with high efficacy in vitro, as well as to know the mechanism of action 
Whole organ complexity and interaction with other organs Ethical considerations To investigate local pathogenic events or the role of different cell types 
Short useful life Differences specific to the species (immune system, hair all over the body, thinner layers of skin, and presence of muscle layer) To investigate the multiple interactions between skin cells, the vascular endothelium and the immune response 
They can be genetically modified 
Complex histology similar to humans 
 Specific Spontaneous Not applicable (NA) NA They are not well-characterized Limited with the appearance of new models 
Genetically Modified NA They allow the study of a specific gene Difficulty of complete reconstruction of the phenotype affecting only 1 gene Discovery of drugs for the treatment of psoriasis directed at a specific gene/pathway or specific phase 
Early embryonic death Investigate factor activity or drugs directed at keratinocytes 
Expensive in terms of time and money Study epidermal hyperplasia 
Induced Cytokine injection They allow the study of a specific cytokine Acute inflammation model (not chronic as in humans) Mechanistic model to detect anti-inflammatory compounds that target the injected cytokine pathway (mainly IL-23), as well as to determine its participation in the development of the psoriatic phenotype 
Chemically (IMQ) Ease of use and obtaining Lack of standardization of the protocol for obtaining the model To study the effect of certain compounds or cell types, as well as evaluate their molecular mechanism 
Acute inflammation model (not chronic as in humans) 
It elicits robust inflammatory and immune responses that are not limited to the skin 
Lower cost Increased thickening of the dermis because the mouse scratches the application site Percutaneous drug absorption studies 
Dehydration and reduction of body weight 
Daily application for more than 2 weeks can cause the death of the animal 
Xenotransplanted or humanized Biopsy of a psoriatic patient Better clinical translation of drugs Limited access to psoriatic skin Ideal for preclinical proof of principle prior to human studies 
Presence of human inflammatory cells in the biopsy before engrafting High time and expense associated with obtaining and transplanting the biopsy To study mechanisms involved in the early development of psoriasis 
More faithful to psoriasis in humans Differences in disease severity between donor grafts To investigate the T-cell based pathogenesis of psoriasis and associated drug development 
It mimics the psoriatic phenotype at both the genetic and immunological levels Absence of de novo recruitment of human peripheral inflammatory cells Evaluation of the effect on the cutaneous nervous system of psoriasiform changes 
Skin obtained by tissue engineering Possibility of obtaining a large number of homogeneously grafted mice Interference of both cytokines and mouse immune cell populations Personalized therapy approach → Allows the generation of a model through certain patients individually 
In vitro 2D Monolayer KT monolayer and KT-THP-1 co-culture Easy access to cells The tested factor is characterized only at the cellular level To investigate the molecular mechanism of the disease, including keratinocyte differentiation and response to stimulators and inhibitors, including small molecules, cytokines, and RNAi 
Inexpensive and straightforward to maintain Does not represent cell-to-cell or cell-to-ECM interactions excluding micro and macro environmental influences 
No use of animals, free of ethical considerations 
Reduced complexity The interaction of individual organs, systems, substances and the actions of the immune system cannot all be considered To assess the effectiveness and safety of new substances with potential therapeutic effects and determine the pharmacological, pharmacokinetic, and toxic properties of the tested compounds 
Detailed characterization of cell biology and responses 
Allows the identification of signaling pathways and mechanisms of action Does not represent histological features 
In vitro 3D RHE Primary NHEKs or immortalized KTs Reproduce the in vivo characteristics of the human skin in terms of epidermal morphology, differentiation, and barrier function Lack of dermal and hypodermal layers and therefore cannot study the interactions between epidermis and dermis To compare KT cell lines regarding the development of psoriatic substitutes 
Reduced complexity compared with FTSE. Lack of appendages and immune cells To evaluate the safety profile and biological activity of different compounds 
No use of animals, free of ethical considerations Do not reflect all the histological features of psoriasis To perform quantitative trait locus analysis 
Impossibility of carrying out studies of vascularization or immune response 
FTSE Collagen-based, DED or self-assembly More biologically and physiologically relevant models, they closely mimic the native skin Lack a fully competent skin barrier and the exact cellular architecture, such as the different skin-resident immune cell types To evaluate the effect or impact of different molecules, compounds, or cytokines on the pathophysiologic characteristic of psoriasis 
Accurately reflect psoriasis hallmarks in the epidermis and dermis layers Lack of appendages To assess the role of different molecules in alleviating symptoms of psoriasis 
No use of animals, free of ethical considerations Time-consuming and labor-intensive To recapitulate inflammatory skin disease and study the immune response in psoriatic skin 
Difficult to reproduce To study the barrier skin function 
To mimic the increased vascularization found in psoriasis 
Commercial Alternative to in-house developed systems Very expensive To evaluate the effect or impact of different molecules, compounds, or cytokines on the pathophysiological characteristics of psoriasis 
More reproducible results 
Fully validated and standardized Low shelf storage time To assess the efficacy of different molecules in alleviating symptoms of psoriasis 
No use of animals, free of ethical considerations Lack of appendages and immune cells 
Ex vivo NA NA Conserve skin complexity including a fully competent skin barrier and presence and/or diversity of immune cells Limited availability To develop skin inflammatory models 
No use of animals, free of ethical considerations Invasive procedure to obtain them To evaluate drug delivery to the skin 
To assess drug penetration studies 
ModelDetailedAdvantagesLimitationsPrincipal applications
In vivo 
 Generals All Zebrafish Human-like genome Ethical considerations Systematic detection of drugs by adding compounds to water 
Easy genetic manipulation Surrounding liquid environment 
Embryo transparency and rapid development with a high number of offspring Lack of epidermal barrier and appendages Study of the participation of certain compounds in chronic inflammation 
Less perception of pain and feeling of stress Presence of scales in adult fish 
Rodents Possibility of studying the interaction between cellular components Differences between strains of mice To determine the efficacy and safety of certain compounds or drugs with high efficacy in vitro, as well as to know the mechanism of action 
Whole organ complexity and interaction with other organs Ethical considerations To investigate local pathogenic events or the role of different cell types 
Short useful life Differences specific to the species (immune system, hair all over the body, thinner layers of skin, and presence of muscle layer) To investigate the multiple interactions between skin cells, the vascular endothelium and the immune response 
They can be genetically modified 
Complex histology similar to humans 
 Specific Spontaneous Not applicable (NA) NA They are not well-characterized Limited with the appearance of new models 
Genetically Modified NA They allow the study of a specific gene Difficulty of complete reconstruction of the phenotype affecting only 1 gene Discovery of drugs for the treatment of psoriasis directed at a specific gene/pathway or specific phase 
Early embryonic death Investigate factor activity or drugs directed at keratinocytes 
Expensive in terms of time and money Study epidermal hyperplasia 
Induced Cytokine injection They allow the study of a specific cytokine Acute inflammation model (not chronic as in humans) Mechanistic model to detect anti-inflammatory compounds that target the injected cytokine pathway (mainly IL-23), as well as to determine its participation in the development of the psoriatic phenotype 
Chemically (IMQ) Ease of use and obtaining Lack of standardization of the protocol for obtaining the model To study the effect of certain compounds or cell types, as well as evaluate their molecular mechanism 
Acute inflammation model (not chronic as in humans) 
It elicits robust inflammatory and immune responses that are not limited to the skin 
Lower cost Increased thickening of the dermis because the mouse scratches the application site Percutaneous drug absorption studies 
Dehydration and reduction of body weight 
Daily application for more than 2 weeks can cause the death of the animal 
Xenotransplanted or humanized Biopsy of a psoriatic patient Better clinical translation of drugs Limited access to psoriatic skin Ideal for preclinical proof of principle prior to human studies 
Presence of human inflammatory cells in the biopsy before engrafting High time and expense associated with obtaining and transplanting the biopsy To study mechanisms involved in the early development of psoriasis 
More faithful to psoriasis in humans Differences in disease severity between donor grafts To investigate the T-cell based pathogenesis of psoriasis and associated drug development 
It mimics the psoriatic phenotype at both the genetic and immunological levels Absence of de novo recruitment of human peripheral inflammatory cells Evaluation of the effect on the cutaneous nervous system of psoriasiform changes 
Skin obtained by tissue engineering Possibility of obtaining a large number of homogeneously grafted mice Interference of both cytokines and mouse immune cell populations Personalized therapy approach → Allows the generation of a model through certain patients individually 
In vitro 2D Monolayer KT monolayer and KT-THP-1 co-culture Easy access to cells The tested factor is characterized only at the cellular level To investigate the molecular mechanism of the disease, including keratinocyte differentiation and response to stimulators and inhibitors, including small molecules, cytokines, and RNAi 
Inexpensive and straightforward to maintain Does not represent cell-to-cell or cell-to-ECM interactions excluding micro and macro environmental influences 
No use of animals, free of ethical considerations 
Reduced complexity The interaction of individual organs, systems, substances and the actions of the immune system cannot all be considered To assess the effectiveness and safety of new substances with potential therapeutic effects and determine the pharmacological, pharmacokinetic, and toxic properties of the tested compounds 
Detailed characterization of cell biology and responses 
Allows the identification of signaling pathways and mechanisms of action Does not represent histological features 
In vitro 3D RHE Primary NHEKs or immortalized KTs Reproduce the in vivo characteristics of the human skin in terms of epidermal morphology, differentiation, and barrier function Lack of dermal and hypodermal layers and therefore cannot study the interactions between epidermis and dermis To compare KT cell lines regarding the development of psoriatic substitutes 
Reduced complexity compared with FTSE. Lack of appendages and immune cells To evaluate the safety profile and biological activity of different compounds 
No use of animals, free of ethical considerations Do not reflect all the histological features of psoriasis To perform quantitative trait locus analysis 
Impossibility of carrying out studies of vascularization or immune response 
FTSE Collagen-based, DED or self-assembly More biologically and physiologically relevant models, they closely mimic the native skin Lack a fully competent skin barrier and the exact cellular architecture, such as the different skin-resident immune cell types To evaluate the effect or impact of different molecules, compounds, or cytokines on the pathophysiologic characteristic of psoriasis 
Accurately reflect psoriasis hallmarks in the epidermis and dermis layers Lack of appendages To assess the role of different molecules in alleviating symptoms of psoriasis 
No use of animals, free of ethical considerations Time-consuming and labor-intensive To recapitulate inflammatory skin disease and study the immune response in psoriatic skin 
Difficult to reproduce To study the barrier skin function 
To mimic the increased vascularization found in psoriasis 
Commercial Alternative to in-house developed systems Very expensive To evaluate the effect or impact of different molecules, compounds, or cytokines on the pathophysiological characteristics of psoriasis 
More reproducible results 
Fully validated and standardized Low shelf storage time To assess the efficacy of different molecules in alleviating symptoms of psoriasis 
No use of animals, free of ethical considerations Lack of appendages and immune cells 
Ex vivo NA NA Conserve skin complexity including a fully competent skin barrier and presence and/or diversity of immune cells Limited availability To develop skin inflammatory models 
No use of animals, free of ethical considerations Invasive procedure to obtain them To evaluate drug delivery to the skin 
To assess drug penetration studies 

DED, de-epidermized dermis; ECM, extracellular matrix; FTSE, full-thickness skin equivalent; IMQ, imiquimod; KTs, keratinocytes; NA, not applicable; NHEK, normal human epidermal keratinocytes; RHE, reconstructed human epidermal equivalent; THP-1, human leukemia monocytic cell line.

Fig. 4.

Decision diagram of in vitro models. FTSE, full-thickness skin equivalents; RHE, reconstructed human epidermal equivalent. Created with Lucid app.

Fig. 4.

Decision diagram of in vitro models. FTSE, full-thickness skin equivalents; RHE, reconstructed human epidermal equivalent. Created with Lucid app.

Close modal

An important aspect of all psoriasis models is whether the results obtained using these models are comparable and consistent with the outcomes obtained from clinical trials. To the best of our knowledge, only one of the studies reviewed in this systematic review has evaluated the efficacy of a compound that has also been evaluated in humans. Tofacitinib is a JAK inhibitor that blocks signaling of key cytokines implicated in the immune response and inflammatory pathways of psoriasis [79]. Results from an in vitro study using a collagen-based FTSE model revealed that psoriasis-like morphologic features were prevented by this inhibitor. This study also showed that tofacitinib pretreatment upregulated genes involved in KTs differentiation and downregulated immune response genes [59]. Results from clinical trials regarding the molecular mechanisms underlying the clinical efficacy of tofacitinib showed that improvements in clinical and histologic features were strongly associated with changes in expression of psoriasis-related genes, which is consistent with the in vitro outcomes [79, 80]. However, human studies provide more details of the disease mechanisms than in vitro studies. For example, in the above study, they also conclude that tofacitinib has a multitiered response in patients with psoriasis by the rapid attenuation of keratinocyte JAK/STAT signaling; removal of keratinocyte-induced cytokine signaling; and inhibition of the IL-23/TH17 pathway.

To overcome the challenges associated with in vitro models, there is increasing focus on the automation of fabrication methods. In addition to saving time, automation would result in the standardization of the process to ensure the reproducibility and consistency of the skin models produced. Furthermore, this automated process could be easily adjusted and modified based on the research needs, while also allowing easy troubleshooting and maintenance [77]. Significant advances have been achieved in this line thanks to different fabrication methods, such as 3D bioprinting where KTs and HFs can be printed directly onto the lesion in a specially defined manner [8, 49].

The development of a platform that evaluates the interaction of the skin with other organs is very interesting for several reasons: (a) to detect unknown side effects of drugs, (b) to evaluate the effects of drugs metabolized by other organs (e.g., the liver), (c) to know the pharmacokinetics of topically administered drugs, and (d) to investigate diseases involving several organs [78]. At this level, the combination of tissue engineering and microfluidic technology has made it possible to create “organ-on-a-chip” to mimic the native tissue microenvironment. Briefly, different cell types are cultured in different chambers on the same platform that communicate with each other through porous membranes. In addition, it has microfluidic devices (valves) that control the nutrition of the cells as well as the exchange of molecules between the different layers, trying to mimic the functionality of skin tissue.

It is important for all skin diseases since the effects are due not only to KTs and HFs, but also to other cell types that make up the skin such as Langerhans and Merkel cells, among others. This technology would allow the incorporation of these cell types, mimic vascularization, and introduce human immune cells [8]. It would also allow the linkage of several organ-on-a-chip models resulting in a body-on-a-chip model. Finally, the combination of this technology with the use of iPSC cells that allow an unlimited number of different cells to be obtained makes it a promising tool for drug development on the road to skin personalized medicine and could replace the use of animal models in the future [42].

Psoriasis skin equivalents are interesting biological tools for screening anti-psoriasis drugs and clarifying psoriasis pathology. However, there are still several challenges to overcome in order to improve their development, complexity, cost, and the time to produce them. In this sense, 3D bioprinting and organ-on-a-chip technologies seem to be the future. Finally, progress in artificial skin models could lead to new psoriasis models which are more similar to humans and therefore reduce animal testing.

It is necessary to combine different preclinical models during drug development due to psoriasis’ heterogeneity.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors have no conflicts of interest to declare.

The work of Ana Ubago-Rodríguez is supported by a contract within a Youth Employment program of the European Social Fund.The work of María I. Quiñones Vico is supported by a FPU predoctoral fellowship (FPU19/05455) from the Ministry of Science, Innovation and Universities of Spain.

Conceptualization: S.A.-S., A.U.-R., and M.I.Q.-V.; search strategy: A.U.-R. and M.I.Q.-V; Article review: A.U.-R., M.I.Q.-V., M.S.-D., R.S.T., A.S.-S., and T.M.-V; expert revision: A.F.-G., and S.A.-S; manuscript preparation: A.U.-R. and M.I.Q.-V. Final approval of the article: all authors.

Additional Information

Ana Ubago-Rodríguez and María I. Quiñones Vico contributed equally to this work.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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