Cytokine-Mediated Molecular Pathophysiology of Hidradenitis Suppurativa: A Narrative Review

Abstract Background: Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the skin that mainly affects the apocrine gland-rich intertriginous areas. The disease manifests as painful nodules, abscesses, and pus-filled tunnels, which can severely impact patient’s quality of life. While diagnosis is clinical, successful treatment options for this condition are limited. There has been an increase in research and clinical trials focusing on biomarkers and cytokines for clinical use. Understanding the potential biomarkers and cytokines implicated in HS pathogenesis may allow efficacious and safe treatment options. Summary: A literature review was conducted on nine biomarkers and cytokines. IL-1, IL-10, IL-17, IL-23, TNF-α, YKL-40, G-CSF, NOD2, and the complement system were identified due to their potential clinical utilization and pathophysiological involvement in HS. Key Messages: With further research expanding our understanding of the pathophysiology of HS and the roles these cytokines and biomarkers play, there is potential for utilization as diagnostic markers or development of antagonists against these specific agents for HS management.


Introduction
Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic cutaneous inflammatory disorder affecting intertriginous areas rich in apocrine glands [1,2].These apocrine gland-rich areas include skinfolds of the axillary, gluteal, inguinal, and perianal regions [1].The disease manifests as painful nodules and abscesses along the affected areas [3].There is an estimated 1-2% prevalence of HS with increasing incidence in the USA [2].HS disproportionately affects female and African-American patients, typically between the ages of 20-40 years old [2].
Genetic predispositions and lifestyle factors play a major role in the pathogenesis of HS.A positive family history has been identified in 30% of patients with this multifactorial condition [1].The dysregulation within the hair follicle subunit leads to cyst formation and disease manifestation [1].Lifestyle factors such as obesity and tobacco smoking play a major role in HS.Around 60% of patients with HS have central obesity, while 90% of patients have a history of smoking [1,2].Obese individuals are believed to be at increased risk of HS due to the increased friction between larger skinfolds causing follicular plugging, metabolic and hormonal changes which may lead to metabolic syndrome, and widespread subclinical inflammation [2].Nicotine in tobacco smoke induces bacterial proliferation, epidermal hyperplasia, potential biofilm formation, and increased proinflammatory cytokine formation [2].The combination of these harmful factors places these patients at increased risk for developing HS.
The pathophysiology behind HS is poorly understood but is thought to be due to a stimulus activating immune cells involved in both the innate and adaptive immune systems [2].Inflammation begins around the hair follicles and gradually forms abscesses and nodules, which may progress to pus-draining tunnels and fistulas [1,3].These lesions form scars at later stages of the disease [1].Depending on the severity of the disease and the residual skin damage, HS negatively impacts patients physically and psychologically [3].Patients may experience irreversible tissue damage, decreased quality of life, decreased mobility due to severe pain and drainage, and systemic inflammation of internal organs [1,2].Due to the drainage, pain, and foul odor, HS causes debilitating effects on patients' personal and professional lives [2].
Currently, there are few effective treatment options to suppress this cutaneous condition other than surgery [3].Proinflammatory cytokines released by immune cells play a vital role in disease progression and worsening of symptoms [2,3].Biomarkers are defined by the World Health Organization (WHO) as "any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease" [4].These biomarkers have promising results for their use in the prognosis, diagnosis, and treatment of various chronic conditions.They have been approved by the US Food and Drug Administration (FDA) for use in the development of new therapeutics [4].A deeper understanding of the role cytokines and biomarkers play in the pathogenesis of HS can potentially expand our current knowledge and management of this debilitating disease.
The aim of this review was to characterize the cytokines and biomarkers implicated in HS in a narrative review.While previous reviews compiled a detailed list of cytokines involved in HS, our review is distinct given that we have gathered additional cytokines and biomarkers obtained in the literature which may play a vital role in HS development and pathogenesis, shown in Figure 1.The focus will be on cytokines and biomarkers involved in HS which may expand our current understanding in diagnosis, prognosis, and managing treatment for this chronic condition.
A literature review was conducted on MEDLINE (PubMed) search engine in December 2022.The keywords included for the search were "hidradenitis suppurativa, cytokines, pathway, biomarkers, cytokine pathways."Using these keywords, 186 search results were found for HS.The articles obtained for this literature review were limited to those published after 2015, yielding 168 search results.Prescreening search results included reviewing the titles of the articles, abstracts, and relevance to our review topic.After screening for studies fitting the inclusion criteria, 34 articles total were included in the final screened results.Articles that characterized cytokines and biomarkers involved in HS were further analyzed and described in this literature review (shown in Tables 1, 2).

HS Cytokines and Their Function
Interleukin-1 Interleukin-1 (IL-1) is a proinflammatory cytokine and immune system activator highly active in HS [3].Cytokines in this interleukin family respond to local or systemic stressors by initiating the innate immune system and inflammatory pathway [5].There are 11 members of the IL-1 family, 7 of these members have proinflammatory effects and four members have antiinflammatory effects [3,5].
Among these members of the IL-1 cytokine family, IL-1β is one of the most highly active inflammatory factors in HS patients.IL-1β levels were increased in the lesions of patients with HS more so than those with psoriasis, a model chronic inflammatory condition [15].The target molecules of the IL-1β pathway were increased in HS lesions [1].Monocytes and macrophages are major cellular players in the innate immune response and producers of IL-1β [3].The inflammasome, a signaling complex in the innate immune system, regulates the activity of caspase-1 and the production of IL-1β [3,15].Activation of IL-1β leads to the production of many chemokines (e.g., CXCL1, CXCL6), matrix metalloproteinases (e.g., MMP1, MMP3), components of the cellular matrix (e.g., COL3A1), and immune cells such as myeloid cells, fibroblasts, natural killer cells, and T-lymphocytes [1,3,15].Dermal fibroblasts have the strongest IL-1 response, induction of signaling molecules, and receptor activity [1,15].Compared to the skin of healthy controls, the lesional, perilesional, and normal skin of patients with HS overexpress IL-1β and its inflammatory pathway mediators [3].The use of IL-1 receptor antagonists to inactivate the IL-1β cytokine response decreased levels of IL-1β and its target molecules [1].Serum amyloid A (SSA1 and SSA2) expression increased in response to IL-1β, resulting in a higher disease severity index in patients with HS [15].Upregulation of the IL-1 cytokine pathway in patients with HS suggests strong evidence for its role in disease pathogenesis and inflammation [3].Proinflammatory cytokine central to regulation of the immune response.They are involved in promoting adhesion factors, thermoregulation, metabolism, and homeostasis [5].

IL-17
Stimulates T-lymphocytes involved in neutrophil activation and mobilization [7].Activation of IL-17 has also been implicated in various inflammatory diseases.
TNF-α Proinflammatory cytokine with a variety of roles, involving regulating immune cells and various inflammatory and autoimmune disease states [9].

Interleukin-10
Interleukin-10 (IL-10) is an anti-inflammatory cytokine involved in the innate and adaptive immune system [3].The IL-10 cytokine family is involved in wound healing, activating the immune response during infections, strengthening the phagocytic response, and regulating homeostasis of the epithelial tissue layers [1,6].This anti-inflammatory cytokine is highly expressed in the skin of HS patients [1,3].
In patients with HS, macrophages are the main sources of IL-10 production [1,9].IL-10 production is stimulated by cytokines and immune detection of microbes or pathogens, leading to activation of T-regulatory cells and suppression of Th1, Th2, and T17 lymphocytes [1,3].By suppressing T-lymphocyte activation and inflammatory cytokine production, IL-10 is an effective suppressor of the immune and inflammatory response [3].Nicotine use increases levels of IL-10 production in HS lesions [1].Increased levels of IL-10 in cutaneous HS lesions may be due to the upregulation of the proinflammatory response occurring in these sites [3].The increase in microbes usually seen in HS sites has lipopolysaccharides on their surface, activating the innate immune system and inflammatory response [9].This compensatory mechanism of IL-10 production suppresses the upregulated inflammatory response.The nodules and abscesses in HS patients contain high numbers of macrophages and neutrophils, supporting this finding [9].

Interleukin-17
Interleukin-17 (IL-17) is a proinflammatory cytokine that plays a major role in the innate immune system by initiating T-lymphocytes to signal neutrophil activation [7].This immune response contributes to the pathogenesis of many different inflammatory diseases, including HS [1,7].Activation of IL-17 may promote disease development, including having a strong pro-osteoclastic effect in rheumatoid arthritis and periodontitis [7].Levels of IL-17 and IL-17 mRNA expression were increased within HS lesions [3,16,17].Compared to healthy controls, there was a 30-fold increase in IL-17A gene expression in the skin of HS patients and a 149-fold increase in IL-17 expression [16].Increased IL-17 levels in the serum correlated with worsening disease severity [3,17].
IL-17 upregulates the expression of proinflammatory molecules, including S100A7, S100A8, S100A9, LL37/ cathelicidin, and human-β-defensin-2 [3,16].These molecules were increased in the perilesional skin of patients with HS and produced from keratinocytes by IL-17 activation [3].Within lesions, neutrophils were the most involved immune cellular players in IL-17 production [16,17].The molecules produced by IL-17 activation are involved in the proliferation of keratinocytes and regulation of the inflammatory pathway [3].Th17 cells were also highly expressed within HS-affected skin [16].The signaling molecules produced by these T-lymphocytes, such as IL-17A and IFN-γ, are enhanced within lesional sites [1].IL-17 expression was enhanced in unaffected skin of HS patients, suggesting subclinical inflammation leading to active lesions seen later in the disease course [3].The initiation of IL-17 stimulation and the activation of additional inflammatory molecules are believed to cause the positive inflammatory feedback loop in HS pathogenesis [16].

Granulocyte colony-stimulating factor
Hormone stimulating the production of granulocyte lineage of cells, specifically neutrophils.It is produced by a variety of cell types in response to inflammation and is even highly expressed in particular cancer cells [12].
Nucleotide-binding oligomerization domain 2 Immune system regulator and inflammasome activator.Recognizes particular components on bacterial membranes to stimulate the immune response [13].
Complement system Important component of the innate immune system that protects against invading microbacteria.Recruits cells for phagocytosis and lysis of target cells and/or organisms [14].
There is overexpression of IL-23 in the papillary and reticular dermis from activated macrophages in HS lesions [1,3,8].Macrophages and dendritic cells are the main producers of IL-23 [3].The toll-like receptors on the surface of bacterial agents activate macrophages, leading to IL-12 and IL-23 secretion and Th17 cell activation [3,8].Activation of these cytokines due to bacterial invasion of affected tissue may be the foundation of the inflammatory feedback loop seen in chronic HS patients [8].Affected skin in HS patients had an increased level of IL-23-producing cells and a 5.2 factor increase of IL-23 mRNA subunit gene expression [8].
Tumor Necrosis Factor-α Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine that acts on multiple cell types [1,9].TNF-α is primarily expressed by macrophages and monocytes [9].TNF-α can trigger the secretion of a variety of chemokines and cytokines in the epidermis, sweat glands, and hair follicles [1,9].These signaling molecules secreted by TNF-α recruit immune cells, such as neutrophils, T-lymphocytes, and monocytes [3,9].This response contributes to the inflammation and immune cell activation seen in damaged cutaneous tissue, which is an important function for the body's natural immune response but is dysregulated in HS [1,3].
TNF-α is elevated in the skin and blood of patients with HS [1,3,9].Increased TNF-α levels are associated with increased disease severity [3,9].While patients with psoriasis have abnormal levels of TNF-α mRNA expression, similar levels of TNF-α gene expression are within HS lesions [1].TNF-α levels in HS patients were higher than in psoriasis patients, suggesting the presence of a massive local inflammatory response involved in HS pathogenesis [9].Anti-TNF-α biologic agents have been used for managing HS previously [1,3,9].Adalimumab is an example of an anti-TNF-α monoclonal antibody approved by the FDA for HS treatment [3].

Potential HS Biomarkers and Their Function
Chitinase-3-Like Protein 1 Chitinase-3-like protein 1 (YKL-40) is an enzyme whose role is poorly understood [10,11].It is a member of the mammalian chitinase family whose enzymatic activity is believed to be lost through time [10].The enzyme is suspected to play a role in signaling pathways, such as inflammation, angiogenesis, carcinogenesis, proliferation, and remodeling [10,11].YKL-40 is involved in cancer, cardiovascular disease, infections, and inflammatory disorders with potential involvement in HS [10,11].
YKL-40 is secreted and activated by cells, such as chondrocytes, synovial cells, neutrophils, macrophages, and monocytes [10,11].The non-lesional skin of patients with HS had similar expression of YKL-40 as with those on healthy skin [10].The lesional skin of HS patients had high cytoplasmic expressions of the YKL-40 enzyme and inflammatory infiltrates within immune cells [10].Higher serum levels of YKL-40 were associated with higher disease severity [11].While biomarkers of inflammation such as CRP and white blood cells were associated with YKL-40 expression, external factors such as age, gender, smoking status, and BMI were not [10,11].Since external factors did not influence YKL-40's expression, it appears to be more specific and useful for HS compared to other proposed biomarkers, such as IL-6, IL-17, IL-23, and S100A8/A9 [10].

Granulocyte Colony-Stimulating Factor
Granulocyte colony-stimulating factor (G-CSF) is a hormone which stimulates the production of cells of the granulocyte lineage [19].Located on chromosome 17, G-CSF is a strong stimulator of neutrophil production, migration, and stimulation [15,19].In HS, inflammation is largely neutrophil-driven, with abscesses and pus-draining tunnels appreciated on clinical exam [15].This major regulator of neutrophil activity is suspected to be highly expressed in patients with HS due to these specific clinical features.Disease severity is positively correlated with increasing G-CSF in the blood [15].Additionally, the homodimer receptor bound to G-CSF was upregulated, with an increase in inflammatory molecules [15,19].With the increased levels of G-CSF in HS abscesses and nodules, this hormone may play a role in the development of painful abscesses, nodules, and foul-smelling purulent drainage classically seen in these patients [15].

Nucleotide-Binding Oligomerization Domain 2
Nucleotide-binding oligomerization domain 2 (NOD2) is a protein of the NOD-like receptor family, which plays an important role as an immune system activator [13,20].NOD2 increases the expression of the inflammasome complex, allowing recognition of peptidoglycans on bacterial surfaces, regulation of cell death, and activation of other immune system mediators [13,20].NOD2 is secreted by monocytes, a cell type of the innate immune system [21].These cells, located on the dermal layer, play an important role in the functioning of the primary skin barrier and wound healing [13].Inappropriate activation of NOD2's signaling pathway has been seen in various chronic inflammatory disorders, such as inflammatory bowel disease [13,20].
With the genetic predisposition in HS patients accounting for 30-40% of familial disease manifestation, along with the dysregulation of the inflammatory response, NOD2 protein gene expression is suspected to play a role in HS pathogenesis [13,20,21].There was an increased expression of NOD2 mRNA in keratinocytes of lesional skin compared to nonlesional skin, with a positive correlation between the expression of other inflammatory mediators as well [13].Bacterial invasion of HS lesional tissue is suspected to cause activation of the NOD2 pathway and thus the innate immune response.Keratinocytes in HS expressed NOD2 and other inflammatory mediators compared to keratinocytes in healthy subjects [13].A Canadian family with two generations of HS with the NOD2 gene mutations was found recently [20].With similar phenotypic symptoms and the lack of typical risk factors, genetic testing resulted in multiple family members with varying levels of expression of the NOD2 gene on chromosome 16 [20].Although these results suggested the need for further genetic studies on NOD2 expression in HS patients, another study detected no expression of the CARD15/NOD2 gene [21].Even with these findings, results of various studies suggest NOD2 expression plays a role in HS pathogenesis and may need to be further studied.

Complement System
The complement system is an important component of the innate immune system which plays a vital role in combatting bacterial infections [14].The activation of this complex system of proteins stimulates the inflammatory response and lysis of the encountered pathogens.C5a, in particular, has a vital role as a chemoattractant of neutrophils and monocytes, contributing to inflammation and further innate immune system activation [22].The complement pathway can also signal B-and T-lymphocytes of the adaptive immune system as well [14].
There were increased levels of C5a and C5b-9 in patients with HS, with greater amounts of complement activation among HS patients compared to healthy subjects [23].Overproduction of C5a is the proposed activator of neutrophils and monocytes, which secrete the proinflammatory cytokine TNF-α [14,23].While these levels did not correlate with patient's disease severities, the concentrations of these complement proteins were detected in much greater quantities than other inflammatory disorders [14,23].Since C5a and C5b-9 were detected at elevated serum concentrations and are one of the various final products of the complement pathway, all three of the complement pathways may be elevated in HS patients [14].There was no difference in complement deposition in HS patients compared to control [24].Similar increases in C5aR1 gene expression were seen in immune cells of HS patients and control subjects, with slightly higher values in HS patients [24].These findings suggest the complement system may play a role in the activation of inflammation seen in HS pathogenesis, amplifying the inflammatory response and mediators, creating a positive feedback loop [14,24].

Conclusion
While the pathophysiology of HS is poorly understood, the activation of immune and inflammatory pathways may play a central role.With the increasing research on biomarkers and pharmaceuticals targeting particular cytokines and monoclonal antibodies, biomarkers and cytokines have promising results for their use in HS management.By identifying cytokines involved in HS, antagonists can be created for treatment of HS with potential significant use in the clinic.For this review, nine cytokines and biomarkers were chosen due to their clinical association and pathophysiological involvement in HS (shown in Fig. 1).
IL-1, IL-17, IL-23, and TNF-α are major proinflammatory cytokines which play a vital role in various inflammatory and autoimmune disorders, including HS. IL-1β is a potent inflammatory marker in patients with HS, with higher levels compared to those seen in psoriasis [15].IL-17, another activator of the innate immune system and inflammatory pathway, upregulates the expression of various proinflammatory molecules in the perilesional skin of HS patients [3].This immune enhancer attracts neutrophils to the affected area, leading to an inflammatory feedback loop and eventual pus formation [16,17].IL-17 is a promotor of disease development [7].Currently, there are multiple IL-17 inhibitors used for other inflammatory disorders, such as psoriasis [16,17].A systematic review examining the effectiveness of different IL-17 inhibitors on HS patients found that two-thirds of the treatment group responded to their assigned anti-IL-17 therapy [25].IL-17 inhibitors such as cJM-122, brodalumab, and ixekizumab are potential drug therapies currently on the market which may be used as treatment, but future studies analyzing their efficacy and safety profile on HS patients' need to be further Cytokines of Hidradenitis Suppurativa Skin Appendage Disord 2024;10:172-179 DOI: 10.1159/000536268 examined [17,25].Secukinumab, an IL-17A inhibitor, is one of the first biologics recently approved by the FDA to treat moderate-to-severe HS.Bimekizumab, an IL-17A and IL-17F inhibitor, is currently in phase III clinical trials for HS.There is sufficient evidence suggesting IL-17 plays a major role in the pathogenesis of HS, making studies analyzing IL-17 inhibitors on HS patients valuable for future therapies [17].
IL-23 indirectly stimulates the inflammatory cascade by activating Th17 cells [8,18].Currently, multiple biologic agents target the IL-23/IL-17 pathway for treatment of other chronic inflammatory diseases [18].IL-23 may be used as a reliable pharmacodynamic and therapeutic biomarker for patients with HS.Specifically, IL-12/ IL-23 agents such as ustekinumab and briakinumab are biologic agents used for other inflammatory disorders, including psoriasis, which may be a future treatment for HS patients [8].There was an 82% success rate using a modified Sartorius score for the treatment population of HS patients using ustekinumab through monitoring changes in severity of affected regions [18].
In recent years, biological agents have been created to target particular cytokines and antibodies for the treatment of inflammatory and autoimmune disorders.TNFα has been a target for these types of therapies, with the anti-TNF-α monoclonal antibody, adalimumab, FDAapproved for HS treatment [3].
IL-10, an anti-inflammatory cytokine, was also highly expressed in the lesional skin of HS patients [1,3].To subside the inflammation and immune reaction taking place within affected tissue, IL-10 secretion is enhanced at these sites.Due to its anti-inflammatory effects, IL-10 has the potential to be used as pharmacodynamic biomarker for clinicians treating HS patients.Monitoring IL-10 levels could be a way to monitor disease progression and maintenance throughout clinical care.
YKL-40, G-CSF, NOD2, and the complement system may serve as guiding clinical tools.High concentrations of the enzyme YKL-40 within the cytoplasm of various immune cells infiltrating lesional skin were found [10].Increased YKL-40 positively correlated with a greater disease burden [11].The capability of detecting expression levels of this enzyme in the clinic can assist in understanding disease severity, management, and treatment options available to patients.A G-CSF inhibitor is currently in phase Ib of a clinical trial and may provide data if this molecule can be used as a therapeutic biomarker [15].The enhanced expressions of YKL-40, G-CSF, and other markers of inflammation positively correlating to disease severity may suggest their possible use as prognostic markers.
NOD2 is an immune-enhancing protein that is elevated in keratinocytes involved in HS lesional skin, correlating to the increased expression of other inflammatory cytokines [13].Using NOD2 protein expression for patients with a family history of HS may be a future clinical option [20].Various molecules of the complement system, such as C5a and C5b-9, were increased in HS patients [23].With the involvement of the complement system suspected in various inflammatory disorders, clinical trials for novel therapies targeting this complex pathway are underway [14,23].Complement proteins, such as C5a and C5b-9, may play a role as a pharmacodynamic biomarker and treatment target for patients with HS.There was a positive treatment response among HS patients who used IFX-1, a monoclonal antibody against C5a [14].With the few pharmacological options currently available for HS treatment, the creation of novel therapies and the use of pharmacodynamic biomarkers in the clinic may be useful as a future treatment strategy.
There are limitations for the use of cytokines and biomarkers to aid in clinical management of HS.Cytokines and potential biomarkers examined in this review were involved in various other chronic inflammatory and autoimmune disorders.This poses the challenge of utilizing these as specific HS biomarkers.Using these markers may be sensitive for HS, but not specific, leaving room for clinical error and difficulty analyzing laboratory results, causing more ambiguity.Varying levels of these biomarkers were present among HS patients, with some dependent on disease severity and others due to tissue sample sites.Further research and clinical trials would be needed to solidify the use of these cytokines and biomarkers in the clinical setting, as well as establish an algorithm for its utilization in diagnosis, prognosis, or managing treatment.
Study limitations include the use of a single search engine for the literature search.Additionally, some of the cytokines and biomarkers examined in this review had limited information and research studies.Other markers identified, which were not included in this review, were deemed not as useful as others but could still be of use in future studies.
There is promising evidence for the future use of biomarkers and cytokines to aid in diagnosis, explore prognosis, and provide promising novel therapeutic options for HS patients.Some of these biologics are established markers or are currently undergoing clinical trials for their use in other inflammatory or autoimmune disorders.YKL-40, G-CSF, NOD2, and the complement system are biomarkers that have not been well characterized in recent HS literature.With our findings in this review, these biomarkers can potentially offer better direction for HS treatment and management in the future.

Table 1 .
HS cytokines and their function Markers Function of markers IL-1

Table 2 .
Potential HS biomarkers and their function