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Correspondence: Lisa A. Beck, Department of Dermatology, University of Rochester Medical Center, 601 Elmwood Ave, Box 697, Rochester, New York 14642, USA.
Sheffield Dermatology Research, Department of Infection, Immunity and Cardiovascular Disease (IICD), The University of Sheffield, The Medical School, Sheffield, United Kingdom
Department of Dermatology, Keio University School of Medicine, Tokyo, JapanLaboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Skin barrier dysfunction, a defining feature of atopic dermatitis (AD), arises from multiple interacting systems. In AD, skin inflammation is caused by host–environment interactions involving keratinocytes as well as tissue-resident immune cells such as type 2 innate lymphoid cells, basophils, mast cells, and T helper type 2 cells, which produce type 2 cytokines, including IL-4, IL-5, IL-13, and IL-31. Type 2 inflammation broadly impacts the expression of genes relevant for barrier function, such as intracellular structural proteins, extracellular lipids, and junctional proteins, and enhances Staphylococcus aureus skin colonization. Systemic anti‒type 2 inflammation therapies may improve dysfunctional skin barrier in AD.
Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease, whose pathogenesis is mediated by interactions between skin barrier impairment and an abnormal immune response featuring enhanced type 2 inflammation (Figure 1). Interactions between keratinocytes (KCs), innate immune cells (e.g., type 2 innate lymphoid cells [ILC2s], dendritic cells, mast cells, basophils, and eosinophils), adaptive immune cells (T and B cells), and an altered epidermal microbiome (with reduction of microbial diversity and predominance of Staphylococcus aureus) all contribute to AD pathogenesis (
Figure 1Type 2 inflammation: primary immune cells, key cytokines and alarmins, exogenous targets, and representative diseases. AD is a predominantly type 2 inflammatory disease. Other type 2 allergic diseases include allergic rhinitis, asthma, CRSwNP, eosinophilic esophagitis, and food allergy. 1IL-25 is also known as IL-17E. AD, atopic dermatitis; CRSwNP, chronic rhinosinusitis with nasal polyps; ILC, innate lymphoid cell; TFH, T-follicular helper; Th, T helper.
CC chemokine ligand 18, an atopic dermatitis-associated and dendritic cell-derived chemokine, is regulated by staphylococcal products and allergen exposure.
). These cytokines, particularly IL-4 and IL-13, act on both structural and immune cells (Figure 1). IL-4 and IL-13 signaling serves as a key initiating pathway for type 2 inflammatory diseases, whereas IL-4 amplifies the allergic inflammation observed in type 2 inflammatory diseases, including AD, asthma, allergic rhinitis, food allergy, and eosinophilic esophagitis (
Report from the National Institute of Allergy and Infectious Diseases workshop on “Atopic dermatitis and the atopic march: mechanisms and interventions.”.
The functions of IL-4 and IL-13 overlap but are not identical (Figure 2). IL-4 and, to a lesser extent, IL-13 regulate class switching and IgE production by plasma cells (
Human B cell clones can be induced to proliferate and to switch to IgE and IgG4 synthesis by interleukin 4 and a signal provided by activated CD4+ T cell clones.
Regulatory effect of extracellular signal-regulated kinases (ERK) on type I collagen synthesis in human dermal fibroblasts stimulated by IL-4 and IL-13.
Protection from fluorescein isothiocyanate-induced fibrosis in IL-13-deficient, but not IL-4-deficient, mice results from impaired collagen synthesis by fibroblasts.
). They also activate Th0 cells, recruit inflammatory effector cells, downregulate the expression of FLG and other skin barrier proteins, and, at least in murine models, favor S. aureus colonization in inflamed skin (
). In addition, IL-4 and IL-13 directly act on sensory neurons, increasing their sensitivity to several pruritogens and contributing to the perpetuation of chronic itch in AD (
Figure 2IL-4 and IL-13 have overlapping but not identical functions; for example, both mediate inflammation and barrier dysfunction through immunologic and structural changes, both enhance pruritogenic pathways, and both promote Staphylococcus aureus colonization in AD. However, IL-4 but not IL-13 promotes the differentiation of Th cells from Th0 to Th2 cells (
TNF-α and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents.
In this paper, we review the role of the components relevant to a functional skin barrier and highlight how skin barrier dysfunction promotes the development of type 2 inflammation and how type 2 inflammation, in turn, affects skin barrier dysfunction.
The Skin Barrier
The epidermis is the only epithelial surface with two barrier structures: the stratum corneum (SC), which is unique to the skin, and tight junctions (TJs), which are present in other epithelia as well (
). Both the SC and the TJs limit penetration of and reaction to microbes, allergens/irritants, and toxins as well as prevent transepidermal water loss (TEWL).
SC
Corneocytes
The SC, the outer layer of the epidermis, is composed of flattened, anucleated KCs (corneocytes) surrounded by a complex lipid-enriched extracellular matrix (Figure 3). Corneocytes are analogous to bricks and lipids to mortar in the original brick and mortar model of the SC (
). This concept has since evolved into a dynamic model in which lipid composition and alignment of the SC allow for adaptation to external factors and are altered in diseases such as AD (
Figure 3The key components of skin showing the differences between normal healthy skin (left side) and AD skin (right side), including the microbiome, corneocytes, antimicrobial peptides, lipids, NMFs, and tight junctions. In the brick and mortar model, the bricks represent corneocytes, and the mortar represents the extracellular lipids and other extracellular matrix components. In the confocal images, green staining represents ZO-1 and CLDN-1, and white represents cell nuclei. Confocal images from AD skin (on the right) show dramatically reduced green staining demonstrating reduced ZO-1 and CLDN-1, compared with normal skin (on the left). 1Confocal images were adapted with permission from
Keratins have both structural and regulatory functions in the epidermis. The more than 20 different epithelial keratins form specific keratin pairs composed of type I (lower molecular weight and acidic) and type II (neutral basic) components (
). Keratin pairs crosslink with other keratin pairs to form keratin filaments, which interact with other proteins and the cell membrane to provide structural stability and flexibility to KCs (
A highly conserved lysine residue on the head domain of type II keratins is essential for the attachment of keratin intermediate filaments to the cornified cell envelope through isopeptide crosslinking by transglutaminases.
The proteins elafin, filaggrin, keratin intermediate filaments, loricrin, and small proline-rich proteins 1 and 2 are isodipeptide cross-linked components of the human epidermal cornified cell envelope.
). In the epidermis, keratin (K) 5 and K14 predominate in the stratum basale, whereas K1 and K10 predominate in the stratum spinosum and higher layers―the change from one pair type to another reflects KC differentiation (
). In contrast, K6, K16, and K17 are associated with the repair of an injured epidermis and are upregulated in inflammatory disorders of the skin, such as AD and psoriasis (
KCs undergo cornification, marking their differentiation into corneocytes; the cells become compact owing to keratin crosslinking, and keratins and other proteins form a cornified envelope that lines the cell membrane (
A highly conserved lysine residue on the head domain of type II keratins is essential for the attachment of keratin intermediate filaments to the cornified cell envelope through isopeptide crosslinking by transglutaminases.
A highly conserved lysine residue on the head domain of type II keratins is essential for the attachment of keratin intermediate filaments to the cornified cell envelope through isopeptide crosslinking by transglutaminases.
The proteins elafin, filaggrin, keratin intermediate filaments, loricrin, and small proline-rich proteins 1 and 2 are isodipeptide cross-linked components of the human epidermal cornified cell envelope.
). Under normal conditions, keratin-filled corneocytes swell and expand with exposure to water, which softens the keratin and allows the SC to bend and stretch (
Keratins have multiple regulatory functions. For example, K1 downregulates the expression and secretion of the inflammatory cytokines IL-18, IL-33, and TSLP as well as damage-associated molecular patterns such as S100A8 and S100A9 (
). K16 downregulates the expression of damage-associated molecular patterns and other inflammatory molecules involved in the innate immune response to skin barrier disruption (
). In contrast, K1 and K10 expression is downregulated by IL-4 and IL-13 in AD lesional skin versus in healthy controls, which might contribute to the SC barrier defects seen in patients with AD and the release of proinflammatory and type 2–promoting alarmins (
Expression of keratin 1, keratin 10, desmoglein 1 and desmocollin 1 in the epidermis: possible downregulation by interleukin-4 and interleukin-13 in atopic dermatitis.
FLG is a key structural protein in KCs. Its precursor pro-FLG is expressed in the stratum granulosum (SG) layer and is the major component of keratohyalin granules (
FLG has multiple functions. It binds to keratin filaments in the KC cytoskeleton, forming an FLG–keratohyalin complex that cross-links to the cornified envelope, transforming KCs into arguably impervious corneocytes (i.e., “bricks”) (
). FLG and NMFs are controlled in a finely balanced process of production, proteolysis, and inhibition that is crucial to skin barrier structure; hydration; and function, including pH regulation, microbial ecology, and possibly even UV protection (
Notably, FLG expression may be reduced in patients with AD without FLG mutations. Type 2 inflammatory mediators, including IL-4, IL-13, IL-31, IL-33, and TSLP, reduce FLG expression (
Thymic stromal lymphopoietin downregulates filaggrin expression by signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) phosphorylation in keratinocytes.
TNF-α and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents.
Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency.
). Repetitive scratching, detergent use, low humidity, exogenous or endogenous proteases, air pollution, and topical and oral corticosteroids can also reduce FLG expression (
). Copy number variants are associated with AD in some but not all populations. For example, in a cohort study in Ireland, reduced copy numbers were more frequent in patients with AD than in normal controls (
FLG deficiency is associated with reductions in SC structure, hydration, antimicrobial function, and epithelial buffering capacity in AD and increases in skin pH, percutaneous absorption, and protease activity (
). FLG-knockdown KCs have reduced levels of K10, TJ proteins (zona occludens [ZO]-1, claudin [CLDN]-1, and occludin), and human β-defensin (hBD)-2; and increased cysteine proteases, which can degrade TJ proteins (
). Reduction in FLG expression reduces the levels of FLG metabolites such as NMFs. This results in an increase in SC pH, which activates serine proteases (
Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency.
). Reduced FLG expression is also linked to increased levels of arachidonic acid and its metabolite 12-hydroxy-eicosatetraenoic acid in KCs, leading to increased inflammation and impairing late epidermal differentiation (
The manifestations of FLG-deficient skin are much more dramatic when combined with the biological actions of IL-4 and IL-13. For example, in an in vitro study, IL-4 and IL-13 stimulation induced spongiosis and increased epidermal thickening, skin pH, and permeability in both normal and FLG-deficient skin equivalents (
). However, in FLG-deficient equivalents, IL-4 and IL-13 decreased the levels of skin barrier proteins (e.g., involucrin and loricrin), TJ proteins (e.g., occludin), and hBD-2 and increased basal layer proliferation rates and TSLP levels to a greater extent than in normal skin equivalents. This suggests that the combination of type 2 immunity and FLG deficiency may promote AD development more than either alone.
NMFs are composed of FLG degradation products (i.e., free amino acids, urocanic acid, and pyrrolidine carboxylic acid), urea, and lactate derived from sweat. Under normal conditions, the decrease in hydration from middle to outer SC levels promotes FLG detachment from the corneocyte envelope and degradation, forming NMFs (
NMFs retain moisture, contributing to barrier function by promoting epidermal hydration through osmotic gradients that allow the movement of water into the corneocytes (
). Decreased SC NMF levels are associated with dry skin and skin diseases such as ichthyosis vulgaris and AD. IL-4 and IL-13 reduce FLG levels and sweat secretion, which thereby affect NMF composition and function (
Loricrin and involucrin are key structural proteins of the cornified envelope that anchor keratin filaments, providing mechanical strength and flexibility to the corneocytes (
A highly conserved lysine residue on the head domain of type II keratins is essential for the attachment of keratin intermediate filaments to the cornified cell envelope through isopeptide crosslinking by transglutaminases.
The proteins elafin, filaggrin, keratin intermediate filaments, loricrin, and small proline-rich proteins 1 and 2 are isodipeptide cross-linked components of the human epidermal cornified cell envelope.
). Both loricrin and involucrin are highly insoluble in late-stage KC differentiation, resulting from disulfide and transglutaminase cross-linking within the molecules and to other proteins in the cell envelope in corneocytes (
The proteins elafin, filaggrin, keratin intermediate filaments, loricrin, and small proline-rich proteins 1 and 2 are isodipeptide cross-linked components of the human epidermal cornified cell envelope.
). Loricrin is more prominent toward the cytoplasmic surface of the envelope, whereas involucrin is localized proximate to the lipid portion of the envelope (
The proteins elafin, filaggrin, keratin intermediate filaments, loricrin, and small proline-rich proteins 1 and 2 are isodipeptide cross-linked components of the human epidermal cornified cell envelope.
), which may account for the reduced levels observed in AD. TNF-α reduces loricrin and involucrin expression, which also explains their reduced levels in psoriasis (
). Interestingly, silencing FLG expression in normal human KCs reduced involucrin expression but upregulated the expression of loricrin and IL-2, IL-4, IL-5, and IL-13 (
Proteases have multiple roles in the SC, mediated by both their direct proteolytic activity and through protease-activated receptors (PARs) (Figure 3). They influence SC cohesion, degrade corneodesmosome proteins (desmogleins and desmocollins) during homeostatic desquamation, regulate lipid synthesis by degrading enzymes that process extracellular lipids, and reduce lipid secretion into the extracellular matrix by stimulating the type 2 plasminogen receptor (
Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity.
). Increased serine protease activity compromises barrier function by increasing the degradation of corneodesmosomes and extracellular lipid-processing enzymes, reducing ceramide production (a characteristic abnormality of AD) (
Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity.
). Both endogenous and exogenous proteases (e.g., from allergens, such as cockroach and dust mites, or from bacteria, such as S. aureus alpha-toxin) activate PAR2 (
). PAR2 activation reduces the expression of TJ proteins (occludin, CLDN-1, and ZO-1) and impairs TJ function, as assessed by reduced transepithelial electrical resistance (owing to a diminished barrier to ions) and increased permeability to small proteins (
). Thus both allergens and cutaneous dysbiosis may promote skin barrier disruption in AD through PAR2-mediated mechanisms. Finally, PAR2 agonists also increase the expression of IL-4 and IL-13 by mast cells, whereas PAR2 inhibition blocks IL-4 and IL-13 expression, decreases skin thickening, and suppresses itching in AD models (
). Of interest, Netherton syndrome, a monogenic AD-like syndrome characterized by the loss of serine protease inhibition due to a mutation in SPINK5 (which codes for the protease inhibitor LEKTI), is associated with kallikrein 5‒mediated PAR2 activation resulting in the production of the pro–type 2 cytokine TSLP by KCs (
Matrix metalloproteinases (MMPs), which affect tissue remodeling and inflammatory cell migration into the epidermis, may also play an important role in AD pathogenesis (
A study of matrix metalloproteinase expression and activity in atopic dermatitis using a novel skin wash sampling assay for functional biomarker analysis.
A study of matrix metalloproteinase expression and activity in atopic dermatitis using a novel skin wash sampling assay for functional biomarker analysis.
Skin barrier lipids are localized in the extracellular matrix surrounding corneocytes and are secreted from lamellar bodies before cornification (Figure 3) (
Attenuated total reflection–Fourier transform infrared spectroscopy as a possible method to investigate biophysical parameters of stratum corneum in vivo.
). Alterations of this packing pattern, resulting from altered lipid composition and lipid-chain shortening, are thought to contribute significantly to skin barrier impairment in AD (
Meta-analysis derived atopic dermatitis (MADAD) transcriptome defines a robust AD signature highlighting the involvement of atherosclerosis and lipid metabolism pathways.
). The expression of the elongases ELOVL1, ELOVL3, and ELOVL6 is reduced in lesional AD skin, resulting in shortened fatty acid chains and increased skin barrier permeability (
). The higher proportion of short fatty acids correlates with changes in lipid organization and skin barrier function and is associated with AD severity (
Interleukin-4 suppresses the enhancement of ceramide synthesis and cutaneous permeability barrier functions induced by tumor necrosis factor-alpha and interferon-gamma in human epidermis.
Sweat is an important component of the skin barrier. Sweat forms a protective layer on the SC surface, contributing to thermoregulation, moisturizing the skin surface, and regulating water retention (
Immunoglobulins coat microorganisms of skin surface: a comparative immunohistochemical and ultrastructural study of cutaneous and oral microbial symbionts.
). TJs prevent sweat ducts from leaking sweat contents into the dermis. CLDN-3 is the most prevalent TJ protein that regulates sweat gland permeability (
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