The Skin Barrier and Moisturization: Function, Disruption, and Mechanisms of Repair

The skin protects the body from external allergens and pathogens. The anatomic layers of the skin are well described, and recently, improved understanding has led to the development of a functional model of the skin barrier [1]. This updated functional model is separated into four interdependent layers – physical, chemical, microbiologic, and immunologic – which work in concert to maintain structural stability and hydration, prevent dysbiosis, and ward inflammation (Table 1).

Barrier disruption is a hallmark of many inflammatory skin diseases and is well-characterized in disease states such as atopic dermatitis (AD) and psoriasis. Moisturizers constitute an important part of the treatment regimen for these disorders, and their efficacy in relation to the skin barrier is now better understood [1]. This narrative review aimed to examine the role of skin barrier via the functional model, and subsequently, to review the mechanisms by which moisturizers influence the functional layers of the skin barrier.

The stratum corneum (SC) forms a barrier against transepidermal water loss (TEWL) and penetration from external immunogens and microbes. The SC is classically described in terms of a “bricks and mortar” construction, whereby maturing keratinocytes flatten, enucleate, and are surrounded by a cornified envelope (CE), forming the so-called “bricks.” The CE refers to a structure composed of two separate envelopes – protein and lipid – and is present just beneath the cytoplasmic membrane of corneocytes [2]. The structural proteins which make up the protein envelope of the CE include involucrin, loricin, keratin intermediate filaments, and desmosomal proteins and are cross-linked by disulfide bonds and isopeptide bonds via transglutaminases [3]. The lipid envelope of the CE is found external to the protein envelope of the CE. It is composed of ceramides which are covalently linked to structural proteins of the protein envelope, including involucrin, envoplakin, and desmoplakin [4]. Together, the protein and lipid envelopes confer additional structural integrity and water impermeability to the physical barrier.

As keratinocytes mature into corneocytes within the SC, the intercellular proteins which link them, desmosomes, are modified into proteins known as corneodesmosomes [5]. Corneodesmosomes serve an important role in strengthening intercellular adhesions between corneocytes and enable the epidermis to undertake significant torsion and stress [6]. Proteins which comprise the extracellular components of corneodesmosomes include two cadherins, desmoglein 1 (DSG 1) and desmocollin 1 (DSC 1), and corneodesmosin (CSDN), which covers the outer surface of the corneodesmosome and further contributes to cell-cell adhesion [7, 8]. Mutations in these proteins drive the pathogenesis of certain genodermatoses; DSG 1 mutations result in severe dermatitis, multiple allergies, and metabolic wasting syndrome (SAM), and mutations in corneodesmosin result in inflammatory type peeling skin disease [9, 10].

A hydrophobic lipid matrix seals the mature corneocytes in place, acting as the “mortar” of this physical barrier. The lipids which compose this matrix are made up of additional ceramides, fatty acids, and cholesterol which associate with the ceramides of the lipid envelope of the CE [2]. Abnormal organization and composition of the lipid matrix result in increased TEWL and allergen penetration [11].

Filaggrin, a molecule which aggregates intercellular keratin filaments, facilitates the flattening of the outer layer of the SC via binding to intracellular keratin. In addition, cross-linking of filaggrin contained within the CE minimizes TEWL and forms a structural barrier against the penetration of allergens and toxins [12, 13]. Filaggrin monomers are cleaved into their component amino acids at the surface of the SC. These amino acids form a hygroscopic natural moisturizing factor (NMF), maintain an acidic pH, and protect against UVB rays [12‒15]. Decreased filaggrin is further implicated in skin barrier dysfunction by decreasing water retention and increasing TEWL [11]. Reduced or absent levels of filaggrin are the major genetic driver of ichthyosis vulgaris and are also associated with AD [16]. Although deficiencies in filaggrin are neither necessary nor sufficient to induce disease in individuals with AD, individuals with null mutations present with more severe AD. Neonates with filaggrin mutations may also be more susceptible to inflammation after contact with cats, and those with filaggrin mutations and AD are more susceptible to inflammation after contact with environmental triggers such as wool [12, 17‒21].

Lamellar bodies reside within the keratinocytes of the stratum granulosum and contain the precursors of the lipid matrix. These lipids are secreted into the intercellular space of the SC at the transition between SG and SC [14, 22]. A ceramide monolayer surrounds the CE of SC corneocytes and forms a scaffold upon which ceramides, free fatty acids, and cholesterol arrange into an intercellular lamellar structure. A physiologic ratio of ceramides, free fatty acids, and cholesterol ensures that the lipid matrix adopts its appropriate 3-dimensional lamellar organization and appropriately functions in both its hydrating and protective capacities.

This effectively seals the flattened corneocytes within a hydrophobic lipid matrix. Lipid barrier dysfunction within the SC is found in disease states such as AD with a reduction from 10% by mass of the SC to 5% in AD [11, 23].

Within the underlying stratum granulosum, tight junctions (TJs) prevent TEWL and maintain distinct solute concentrations between layers [13, 14, 24‒26]. TJs limit the paracellular transport of solutes and TEWL [14, 22]. TJs also function in a reactive manner to barrier disruption; their expression is increased in response to toll-like receptor (TLR) signaling. TJ function is linked to other components of the physical skin barrier. Murine claudin-1 (a key TJ protein) knockout models have concurrent decreased filaggrin expression, lipid matrix disorganization, and increased skin inflammatory response [27]. Furuse et al. [28] demonstrated that claudin-1 null mice die within 1 day of birth with severely disrupted barrier function. De Benedetto et al. [29] further showed that expression of claudin-1 varies inversely with levels of IgE and eosinophils in AD patients, suggesting an association between TJ function and barrier disruption in AD. TJ dysfunction can also contribute to chronic itch. Takahashi et al. showed that sensory nerve endings are normally found underneath TJs, but that in AD, this protection is disrupted, leading to improper activation and sensitization. Importantly, pruning of nerve endings occurred at sites of TJ formation in healthy murine skin but was disrupted in models of chronic itch, suggesting that TJ dysfunction may expose nerve endings and potentiate chronic itch [30].

The components of the physical barrier all serve to preserve hydration within the skin. An overview of the distribution of water within the epidermis is needed to understand the mechanisms by which moisturizers bolster the physical barrier, and, therefore, maintain adequate skin hydration. In general, water content increases in the deeper layers of the epidermis, with the greatest increase in water content observed in the transition from the SC to the stratum granulosum [31]. Within the SC, water is found predominantly in two general locations. First, water may bind to the NMF, a group of hygroscopic compounds which pull water from within and outside the skin and lipids within the SC. Water associated with the NMF or SC lipids generally varies with the water content present in the external environment [32]. Second, water may be bound to intracellular keratin; this portion of water generally remains consistent, save for instances of skin barrier compromise in which this water may be lost to the environment [32].

The chemical layer of the skin barrier consists of lipids, NMF, and compounds which maintain an acidic pH. These elements ensure that the skin barrier is adequately hydrated, protected from dysbiosis, and at a pH which optimizes enzymatic function in cornification, desquamation, and lipid synthesis [33].

Lipids contribute to both the physical and chemical skin barrier and are derived from sebocytes, keratinocytes, and commensal microbes [34]. They protect the SC from TEWL, UV rays, oxidation, and pathogens; they are also a component of biochemical signaling pathways and skin barrier repair [11, 34, 35]. Lipids interact with the microbiome layer through their anti-bacterial effects against Staphylococcus spp. Other gram-positive organisms solidify the physical barrier by acting as an extracellular “mortar” within the SC [34, 35].

Skin pH is another important component of the chemical barrier. The concept of an acid mantle is well-described and refers to the components of the skin barrier which maintain the physiologic pH of the skin between 4 and 6. This acidic pH supports homeostasis, an antimicrobial environment, and both barrier integrity and recovery [36‒40]. In addition, the acidic environment of the skin provides protection against dysbiosis. Commensal organisms favor acidic pH, and pathogenic organisms, such as Staphylococcus aureus, favor a more neutral pH [36, 39].

Enzymatic processes crucial to skin barrier function, such as regeneration, desquamation, and cutaneous lipid metabolism, are all also linked to skin pH. Desquamation of the skin is mediated by proteases, such as Kallikrein-related peptidases (KLKs) and cathepsins which disrupt the connections between corneodesmosomes in the SC. The serine protease activity of KLKs is inhibited by certain serine protease inhibitors, such as skin-derived anti-leukoprotease(SKALP), serine-specific inhibitor Kazal type 5 (SPINK5), and lympho-epithelial Kazal-type-related inhibitor (LEKTI), thus establishing a balance in the process of desquamation [41]. Skin pH influences the enzymes such as cathepsin D, and maximum enzyme activity occurs at a pH of 3.

In addition to influencing enzyme activity in desquamation, skin pH is a critical mediator of lipid metabolism and lipid bilayer structure within the SC. SC ceramide precursors, including glucosylceramides and sphingomyelin are stored within lamellar bodies within the SG [42, 43]. Enzymatic modification of the glucosylceramides and sphingomyelin by β-glucocerebrosidase and acid sphingomyelinase, respectively, during secretion at the junction between the SG and SC yields the observed ceramides which constitute an important component of the intercellular lipids of the SC [11, 42]. pH is an important determinant of the efficacy of this process – acidic pH promotes optimal activity of both β-glucocerebrosidase and acid sphingomyelinase, and neutralizing SC pH was shown to reduce activity of β-glucocerebrosidase [44]. Furthermore, acidification of the SC in murine models of AD was shown to increase β-glucocerebrosidase activity, ceramide production, lamellar body secretion, and promote optimal lipid bilayer structure within the SC [45]. In response to skin barrier disruption, TNF signaling increases activity of acid and neutral sphingomyelinase, which in turn increases ceramide production and barrier integrity [46]. Sphingomyelinase functions optimally at an acidic pH, further emphasizing the importance of skin pH in barrier regeneration and repair.

The structure of the lipid bilayer is also affected by the surface pH. At a surface pH of 5, the head groups of lipids do not experience significant repulsion from one another and are able to assemble into a bilayer structure; in AD, increased surface pH disturbs the lipid bilayer structure of the SC and increases barrier permeability [47].

Neutralization of skin pH in mice upregulated the expression of serine protease enzymes and impaired corneocyte adhesion [44]. Exposure to harsh, alkaline chemicals increases the risk for developing contact dermatitis, especially in individuals with comorbid AD. Kim et al. [48] showed that application of skin care products of varying pH (3, 5, 8) for 5 weeks followed by 1% sodium lauryl sulfate (SLS) challenge significantly increased TEWL in the group which applied the alkaline product. Korting and Schmid conducted cross-over studies in which subjects washed their forehead and forearms with an alkaline soap followed by an acidic synthetic detergent (syndet), or vice versa. Subjects who washed with the alkaline soap not only saw an increase in skin pH but also saw greater bacterial counts of Propionibacteria compared to subjects who used the acidic syndet. While pH returned to baseline after 2 h, sustained washing over weeks produced measurable changes in both skin pH and bacterial cell counts [49, 50].

One of the ultimate goals of the skin barrier was to maintain hydration, and it is a key marker for therapeutic response in inflammatory skin disorders. The primary methods by which moisturization of the barrier are secured are through the moisture-sealing barrier formed by the intercellular SC lipids and the hygroscopic agents on the surface of the skin. Within the SC are the intercellular lipids, which form a matrix that secures moisture within the epidermis. Filaggrin is an important component of both aspects, through both its breakdown products and its role in lipid processing within the SC. The breakdown products of filaggrin make up a large percentage of these hygroscopic compounds, collectively known as the “natural moisturizing factor” (NMF), which pulls moisture from the dermis into the SC. Profilaggrin is composed largely of l-histidine, and subsequent proteolysis of filaggrin releases large quantities of l-histidine which contribute to the NMF [51, 52]. Oral l-histidine supplementation significantly reduced SCORAD by 34% and 32% at 4- and 8-weeks treatment duration compared to placebo in a pilot study of adults with moderate AD [53]. In children (mean age 3.4 years) with mild-to-moderate AD, oral l-histidine supplementation significantly reduced SCORAD by 49% at 12-weeks treatment duration compared to placebo [52].

Other factors which make up the NMF include pyrrolidone carboxylic acid, urocanic acid, lactic acid, urea, citrate, and various sugars. Several of these compounds are frequently incorporated into moisturizers to improve skin barrier function [40, 54]. Decreased NMF content adversely impacts the hydration of the skin barrier. Soltanipoor et al. [55] found that exposure to n-propanol decreases NMF content and skin hydration, and also results in a small corresponding increase in TEWL. Angelova-Fischer et al. [56] found that sodium hydroxide, and the detergent SLS significantly decreased NMF and slightly increased TEWL in both patients with AD and in healthy controls.

A diverse microbiome layer consisting of commensal microorganisms and bacteria such as Staphylococcus, Corynebacterium, Propionibacterium, Brevibacterium, and Micrococcus colonizes the outer surface of the epidermis [57]. The composition of the cutaneous flora is dependent on a variety of factors such as pH, temperature, anatomic location, hormone status, and age [58].

A rapid expansion in microbial diversity occurs in the transition from in utero to birth with simultaneous maturation of innate and adaptive immunologic pathways. This primes the host to recognize commensal skin organisms and prevents deleterious immune and inflammatory responses from occurring in response to these organisms, possibly through TLR-2 receptor sensitization in the case of Staphylococcus epidermidis [59].

Commensal microbes interact with the chemical and immunologic layers of the skin barrier by signaling host keratinocytes to produce antimicrobial peptides (AMPs) [33]. These include human beta-defensins (hBDs) and cathelicidins which prevent the growth of microorganisms [24, 60, 61]. In addition to their antimicrobial properties, AMPs are also involved in immune regulatory processes, keratinocyte activation, and skin barrier function [22, 33, 60, 62, 63]. hBDs are contained within the lamellar bodies of keratinocytes and secreted into the extracellular space of the SC. They have antimicrobial activity against a wide variety of microorganisms including E. coli, P. aeruginosa, C. albicans, S. aureus, and other bacteria and fungi. Some hBDs, such as hBD-1, are constitutively expressed, while others including hBD-2, -3, and -4 are upregulated in response to pro-inflammatory cytokines and under certain inflammatory conditions, such as psoriasis [33, 60]. AMPs are produced by commensal microorganisms such as S. epidermidis and Staphylococcus hominis have been shown to be microbicidal to pathogenic S. aureus. [64].

In addition to their antimicrobial effects, AMPs also are involved in linking innate and adaptive immune pathways. AMPs can induce the migration of innate inflammatory cell types and call for the arrival of dendritic cells and T cells during the times of infection. In addition, they may also be involved in antibody class switching [33, 65]. AMPs may help fortify the skin barrier by upregulating proteins which make up TJs. Akiyama et al. showed that the cathelicidin LL-37 increased expression of claudins and occludins while Hattori et al. showed that S100a7 had similar effects in the upregulation of TJ proteins [62, 63]. These studies also showed that AMPs can increase the expression of keratinocyte differentiation markers, such as filaggrin, involucrin, keratin 1 and 10, and transglutaminase 1 [62].

Colonization of the epidermis with commensal microbes limits both space and nutrients for other, potentially pathogenic microbes [22]. S. epidermidis, a healthy commensal organism, upregulates TJ proteins and helps maintain the physical barrier; demonstrating further interdependence between the functional layers [22].

In disease states such as AD, S. aureus characterizes the dysbiosis of the outer microbiome layer. It is a marker of disease severity and may be a herald for disease onset [66, 67]. S. aureus directly penetrates and activates the immune system, stimulating IL-4, IL-13, and IL-22 secretion [68]. Enterotoxins and alpha toxin produced by S. aureus contribute to cell lysis of keratinocytes and immune cell activation [69]. S. aureus may also influence type 2 immune pathways characteristic of AD through second immunoglobulin-binding protein (Sbi), which was shown to induce IL-33 release from human keratinocyte explants in a manner independent from TLR signaling [70]. Other mechanisms of S. aureus-induced barrier disruption include superantigen release, which stimulates a T cell-mediated inflammatory response and directly damages the skin barrier and keratinocyte secretion of serine proteases [68, 71, 72].

Immune cells maintain skin barrier homeostasis by recognizing barrier disruption, communicating with commensal microbes, and initiating immune pathways. Resident and recruited immune cells of both innate and adaptive cell types make up the skin immune barrier [73, 74]. The innate immune cells of the skin constantly sample the external environment through a variety of pattern recognition receptors and selectively initiate signaling responses to barrier disruptors. Resident cells such as epidermal Langerhans cells (LCs), dermal dendritic cells (DCs), resident T cells, and keratinocytes themselves are capable of initiating signaling pathway responses to barrier injury.

An important interplay exists between the immunologic and microbiome layers of the skin barrier to prevent dysbiosis. Innate and adaptive immune responses, as well as competition from commensal organisms, ensure that populations of potentially pathogenic organisms, such as S. aureus, do not grow to inflammatory proportions [74]. In mice, commensals modulate immune responses; S. epidermidis colonization induces IL-17 signaling, CD8+ T-cell migration, and increased barrier immunity to C. albicans [75]. The host’s unique population of immune cells also influences the composition of the commensal microbiome; individuals with primary immunodeficiencies have significantly altered commensal microbiomes [76].

Keratinocytes themselves help maintain an epidermal population of immune cells, primarily through cytokine signaling. Resident memory T cells (Trm) are retained via IL-7, IL-15, and TGF-B; LCs via colony-stimulating factor 1 ligand and TGF-B, and macrophages via IL-34 [74]. Keratinocytes are outfitted with a variety of pattern recognition receptors capable of recognizing pathogen-associated molecular patterns and damage-associated molecular patterns linked to microbial invasion and mechanical stressors, respectively. This results in NF-kB or MAPK-mediated second messenger activation, transcription of pro-inflammatory genes, cytokine signaling, and cell-mediated inflammatory responses [74].

LCs have been shown by Seneschal et al. [77] to have an important role in linking the innate and adaptive immune responses in the skin via their interactions with resident regulatory and effector memory T cells. Resident memory T cells (Trm) are present in both epidermis and dermis and sense physical barrier and microbiome disruption. Their concentration is highest at sites of initial infection and importantly has been shown to distribute across the skin surface to grant immunity to locations outside of the primary site of infection [73, 78]. Kobayashi et al. [74] posit that site-specific populations of immune cells and cutaneous microbiota could be a potential cause of varied immune responses seen across topologically differing skin sites.

Disruptions to the immune barrier are well-established in the literature for inflammatory skin disease. In AD, mutations to genes coding for proteins such as filaggrin and claudin-1 result in structural weakness in the SC and increased permeability of the TJ barrier, respectively. Increased permeability results in antigen penetration, DC activation and TSLP release, ultimately causing a type 2 adaptive immune response against the epidermis [79‒81]. Type 2 cytokines IL-4 and IL-13 further exacerbate barrier dysfunction by inhibiting expression of filaggrin and disrupting TJs [80, 82]. B-cell activation by IL-4 produces IgE against the invading antigens, but may also produce IgE against self-antigens as well. TSLP and IgE invoke pruritus, which causes scratching and further barrier disruption as outlined previously [81].

A similar cycle of inflammation and barrier disruption is present in psoriasis. Pro-inflammatory dendritic cells release IL-23, resulting in IL-17 release from T cells. IL-17 activates epidermal keratinocytes to release pro-inflammatory cytokines IL-1, IL-6, CXCL1, and CCL20, all of which further psoriatic inflammation [83, 84].

Moisturizers are a mainstay of treatment for AD and other inflammatory skin disorders. Daily use of moisturizers containing some combination of emollient, humectant, and occlusive ingredients improves barrier function and reduces the need for topical corticosteroid therapy in AD (Table 1) [85]. As the skin barrier becomes further understood, moisturizers with components targeting specific barrier deficiencies may be developed (Table 2). Currently, the efficacy of moisturizers can be understood through the functional barrier model of the skin.

The occlusive, emollient, and humectant properties of moisturizers support the physical skin barrier. Ubiquitously used occlusives, such a petrolatum, have been used in newborns to bolster their developing skin barrier, and its mechanisms are now better understood. Czarnowicki et al. found that application of petrolatum not only added an occlusive barrier to the epidermis but also upregulated expression of AMPs and keratinocyte differentiation markers (e.g., filaggrin and loricrin) and decreased levels of epidermal T cells [86].

A single application of emollient-containing lipids of similar composition and arrangement to the intercellular lamellar matrix was shown to significantly increase SC hydration at 24 h compared to a control cream [87]. Topical application of physiologic lipids (ceramides, free fatty acids, and cholesterol) leads to incorporation into lamellar bodies, supplementing synthesis and subsequent secretion of lipids into the intercellular lipid matrix. An emollient containing this trio of lipids with an increased ceramide component was shown to improve hydration and reduce TEWL in patients with AD compared to control, petrolatum-based occlusive moisturizers [88].

“Emollient” may also be used to describe emulsifying ingredients within moisturizers which contribute to how easily the product is able to be spread. These compounds are typically alcohols or esters, specific formulations of which render the moisturizer either greasy, less easily spread, and more occlusive, or thinner, more easily spread, and less occlusive.

Emulsifying ingredients contained within lotions and creams may contribute to barrier disruption by altering the structure of SC lipids. Anionic emulsifiers, such as SLS, bind to SC lipids, increase the mobility between the lipid bilayers, and decrease its integrity such that barrier function may be compromised [89]. Additionally, SLS has been shown to increase inflammatory cytokine expression on repeated exposure, suggesting that this barrier disruption may result in irritation [90]. It is important to recognize that non-ionic emulsifiers, such as cetylstearyl alcohol are less barrier disruptive than cationic emulsifiers such as polyoxyethylene-20-glycerol monostearate (PEG-20-GMS) and much less barrier disruptive than SLS, which were both shown to remove SC lipids to a greater extent than cetylstearyl alcohol [91].

Humectants draw water from the dermis into the SC and include many compounds found in NMF [92]. Hydrating compounds upregulate the expression of aquaporin channels, claudins, and filaggrin, thereby increasing hydration and preventing water loss [93]. Samadi et al. [93] found that humectant-containing moisturizers significantly improved moisture content compared to control (no product applied) at 2 weeks. It was also found that both occlusive and ceramide-containing moisturizers significantly improved TEWL at 2 weeks, likely due to the application of a hydrophobic layer on the SC and incorporation of a physiologic barrier lipid into the SC, respectively [93].

Studies by Buraczewska et al. examined the effects of two different moisturizers had on mRNA expression of genes involved in keratinocyte differentiation, desquamation, and barrier lipid synthesis. While one moisturizer decreased TEWL, another moisturizer increased TEWL through increase in expression of serine protease genes and a decrease in expression of lipid synthesis genes. Barrier function should be taken into consideration when choosing a moisturizer, as potential worsening of disease may occur [94].

The chemical layer of the skin barrier is made up of hydrating compounds, AMPs, and an acidic pH. Urea, an NMF component and breakdown product of filaggrin, has been shown to improve skin hydration and reduce TEWL when incorporated into moisturizers [32, 95]. In addition to its hygroscopic effects as part of the NMF, it has been suggested to stabilize the SC lipid matrix by assimilating into hydrophilic spaces within lipid bilayers; thus stabilizing the matrix and reducing TEWL [96]. Urea may alter gene expression as well, as inhibition of epidermal urea transporters results in decreased mRNA and protein levels of structural proteins, lipid synthesis enzymes, and AMPs. A 2015 meta-analysis found that moisturizers containing urea had the best evidence for improving the SCORing Atopic Dermatitis measure (SCORAD), TEWL, and hydration [97]. Many studies demonstrating its efficacy as a hydrating ingredient have safely used urea in concentrations of less than 10% with no significant adverse effects reported [95]. At concentrations greater than 20%, urea may exert a keratinolytic effect, breaking down hydrogen bonds within keratin to allow increased binding of water molecules [98].

The acidic environment of the SC is maintained by fatty acids, lactic acid, amino acids, and the protein products of filaggrin breakdown [99, 100]. Levels of these components are decreased in inflammatory skin disease such as AD, contributing to a neutral pH which impairs barrier function and predisposes the skin to colonization with pathogenic S. aureus [100]. Furthermore, neutralization of the SC results in serine protease activation, reduced activity of lipid synthesis enzymes, and disruption of corneodesmosomes [101]. Moisturizers which maintain an acidic SC may therefore represent an important component of barrier maintenance.

In addition to the pH of the moisturizer, the buffer capacity of the moisturizer also ultimately influences the pH of the SC. Buffering capacity refers to the degree of acidic or basic insult which can be sustained without a change in pH [47]. Regarding the SC, urocanic acid and its breakdown products, free fatty acids, sodium-hydrogen exchange transporters, lactate, carbonic acid, hydroxide, carboxylate, various amines, amino acids, and peptides all contribute to the SC buffer capacity [47, 102]. Buffering capacity also plays a role in determining the effectiveness of moisturizers, as moisturizers with a higher buffer capacity will be able to maintain the desired pH of the SC for a longer duration of time [47].

Acidic moisturizer applied twice-daily to AD-like murine skin reduced the development of AD-like lesions and subsequent allergic respiratory illness, suggesting a therapeutic link between SC acidification, barrier function, and prevention of the atopic march [103]. SC acidification has been shown to clinically improve skin barrier function as well. Middleton in 1976 observed that skin treated with moisturizers containing sodium lactate adjusted to pH 4-reduced hand dryness and flakiness compared to control moisturizer [104]. Rawlings et al. found that topical application of a 4% l-lactic acid moisturizer significantly increased SC ceramide content and barrier resilience, measured via tape-stripping and subsequent TEWL, compared to application of a vehicle without lactic acid [105]. A recent study using a moisturizer of pH 4.5 in patients with AD found a trend toward improved SCORAD and TEWL compared to a control commercial moisturizer [106].

Topical application of personal care and beauty products has been shown to alter the composition of the cutaneous microbiome [107]. While different products have variable effects on the cutaneous microbiome, moisturizers can help protect against harm to the skin barrier caused by overgrowth of pathogenic organisms like S. aureus. In AD, the skin is predisposed to S. aureus colonization due to a dearth of AMPs and access to nutrients exposed by a defective skin barrier [108]. Emollient therapy has been shown to shift cutaneous bacterial populations, reducing Staphylococcus and increasing overall diversity [108, 109]. However, moisturizers which contain parabens may promote dysbiosis and worsen AD. Isolates of Roseomonas mucosa, a gram-negative bacteria, taken from healthy volunteers reduced SCORAD by >50% in an open-label, phase 1/2 study of adults and children with AD in 10 of the 15 participants [110]. In this same study, it was also found that a paraben mix inhibited the R. mucosa isolates taken from the healthy volunteers to a greater extent than it inhibited S. aureus, suggesting that commonly encountered parabens in moisturizers and other products may contribute to dysbiosis [110].

Skin microbiome composition was analyzed after twice-daily application of an emollient containing shea butter, niacinamide, and thermal spring water [109]. Prior to treatment, Staphylococcus were found to be the most abundant species on affected skin. After 84 days of twice-daily emollient therapy, patients whose SCORAD improved were also found to have increased diversity and decreased Staphylococcus in lesional skin [109]. A study which looked at the application of an emollient to infant skin within 3 weeks of birth and analyzed bacterial composition at 6 months compared to control found lower pH and increased bacterial diversity in the treatment arm, specifically noting an increase in Staphylococcus salivarius [111]. While a specific mechanism for emollient application increasing microbial diversity is yet to be elucidated, it is reasonable to assume that skin barrier repair may allow for repopulation with commensal organisms and restriction of Staphylococcal growth. Further studies which analyze specific markers of skin barrier health in relation microbial diversity following moisturizer application are required.

The immunologic barrier is closely linked to the microbiome, evidenced by crosstalk between the cutaneous microbiome and skin immune layer and can be protected and repaired through moisturizer use. As previously discussed, application of petrolatum was shown to decrease levels of T cells in both lesional and non-lesional AD skin. This same study found that petrolatum application increases levels of AMPs, such as LL-37, which in turn upregulates innate immune gene expression and may prevent infection [86].

The extent of the inflammatory response initiated by barrier disruption may extend beyond skin inflammation and may also help explain the association seen between AD and food allergy. Galand et al. found that both nonallergic humans and mice with disrupted skin barriers (via scratching and tape-stripping, respectively) were found to have increased local levels of IL-33 at sites of disruption. Murine models were subsequently epicutaneously sensitized to ovalbumin at tape-stripped sites. Models which lacked the IL-33-binding mast cell receptor ST2 were protected against anaphylaxis upon oral challenge with ovalbumin compared to wild-type mice. As human subjects also experienced increases in IL-33 in scratched skin, it is hypothesized that regular moisturization during infancy may help curtail the incidence of food allergy in this population [112].

Studies by Simpson and Horimukai report a statistically significant reduction in AD and allergic sensitization in infants who received daily emollient application, but the recently published barrier enhancement for eczema prevention and Preventing Atopic Dermatitis and Allergies (PreventADALL) trials did not find a benefit for emollient therapy in the prevention of AD or allergy [113‒116]. Regardless, there is an established benefit for emollient use in skin barrier repair, as it helps curtail the inflammatory loop established and potentiated by barrier disruption. Interestingly, Ye et al. [117] report that use of a ceramide-containing emollient in aged individuals not only measurably improved barrier function but also that circulating levels of inflammatory cytokines implicated in age-related chronic inflammation such as IL-1B, IL-6, and TNF-a were also decreased.

This review aimed to synthesize the literature regarding the updated functional model of the skin barrier and to highlight the methods by which moisturizers influence and improve the skin barrier. There is an exciting possibility that emerging products will utilize points of skin barrier disruption as therapeutic targets: newer moisturizers have already been developed with these targets in mind. Moisturizers are a pivotal component of treatment regimens for skin disease, and as our understanding of the skin barrier grows, sophisticated formulations may be developed which target patterns of barrier disruption observed in individual disease phenotypes.

Dr. Vivian Shi is a stock shareholder of Learn Health and has served as an advisory board member, investigator, and/or received research funding from Sanofi Genzyme, Regeneron, AbbVie, Eli Lilly, Novartis, SUN Pharma, LEO Pharma, Pfizer, Menlo Therapeutics, Burt’s Bees, Galderma, Altus Lab, MYOR, Polyfin, GpSkin, and Skin Actives Scientific. Dr. Peter Lio reports research grants/funding from AOBiome, Regeneron/Sanofi Genzyme, and AbbVie is on the speaker’s bureau for Regeneron/Sanofi Genzyme, Pfizer, Eli Lilly, Galderma, and L’Oreal; reports consulting/advisory boards for UCB, Dermavant, Regeneron/Sanofi Genzyme, Dermira, Pfizer, LEO Pharmaceuticals, AbbVie, Kiniksa, Eli Lilly, Micreos (stock options), L’Oreal, Pierre-Fabre, Johnson & Johnson, Level Ex, Unilever, Menlo Therapeutics, Theraplex, IntraDerm, Exeltis, AOBiome, Realm Therapeutics, Altus Labs (stock options), Galderma, Verrica, Arbonne, Amyris, Bodewell, Burt's Bees, and Kimberly-Clark. In addition, Dr. Lio has a patent pending for a Theraplex product with royalties paid and is a Board member and Scientific Advisory Committee Member of the National Eczema Association and an investor at LearnSkin. Dr. Neha Chandan and Jeffrey Rajkumar have no conflicts of interest to disclose.

The authors have no funding sources to disclose.

Jeffrey Rajkumar, Dr. Neha Chandan, Dr. Peter Lio, and Dr. Vivian Shi contributed to the conception of this review article, the literature review, manuscript drafting, and manuscript editing. All authors participated in drafting this article and critically reviewed the article prior to its completion. All authors agreed upon the final version of the manuscript to be submitted.