Type 2 Inflammation Contributes to Skin Barrier Dysfunction in Atopic Dermatitis

Abstract

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.

Keywords: AD, atopic dermatitis; AMP, antimicrobial peptide; CLDN, claudin; FFA, free fatty acid; ILC2, type 2 innate lymphoid cell; Jaki, Jak inhibitor; K, keratin; KC, keratinocyte; MMP, matrix metalloproteinase; NMF, natural moisturizing factor; PAR, protease-activated receptor; PDE-4, phosphodiesterase-4; SC, stratum corneum; SG, stratum granulosum; TCI, topical calcineurin inhibitor; TCS, topical corticosteroid; TEWL, transepidermal water loss; TJ, tight junction; TLR, toll-like receptor; TNF-α, tumor necrosis factor alpha; TYK, tyrosine kinase; Th, T helper; ZO, zona occludens; hBD, human β-defensin.

Figure 1

Type 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.

Figure 2

IL-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 (Berdyshev et al., 2018; Campion et al., 2019; Chen et al., 2004; Danso et al., 2014; Finkelman et al., 1988; Gandhi et al., 2016; Goleva et al., 2019; Guttman-Yassky et al., 2019a; Hamilton et al., 2021, 2014; Howell et al., 2008; Jessup et al., 2008; Kim et al., 2008; Paul, 2015; Suárez-Fariñas et al., 2013; Swain et al., 1990; Zheng et al., 2009). AD, atopic dermatitis; DC, dendritic cell; ILC, innate lymphoid cell; Th, T helper.

Figure 3

The 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 Takahashi et al. (2019) (http://creativecommons.org/licenses/by/4.0; modified), courtesy of Takaharu Okada at RIKEN IMS (Yokohama, Japan). ²Confocal images were provided with permission from De Benedetto et al. (2011a). AD, atopic dermatitis; CLDN, claudin; KLK, kallikrein; MMP, matrix metalloproteinase; NMF, natural moisturizing factor; SB, stratum basale; SC, stratum corneum; SG, stratum granulosum; SS, stratum spinosum; ZO, zona occludens.

Figure 4

Skin barrier disruption and type 2 inflammation in AD. In acute AD, barrier defects in compromised skin lead to increased permeability and penetration of environmental factors (e.g., microbes, allergens) (1). Skin barrier defects and infiltration of immune cells lead to type 2‒mediated production of inflammatory cytokines (e.g., IL-4, IL-13, IL-31) (2). In the epidermis, epithelial barriers predisposed to type 2‒mediated disease are characterized by barrier disruption and greater numbers of Langerhans cells with dendrites penetrating through TJs (3). In chronic AD, type 2 inflammatory responses lead to epithelial remodeling and proliferation (e.g., FLG and other proteins, lipids, and AMPs) (4). The inflammatory cascade is further intensified by IL-4‒ and IL-13‒mediated immune responses (5). AD, atopic dermatitis; AMP, antimicrobial peptide; CCL17, C–C motif chemokine ligand 17 (thymus and activation-regulated chemokine); ILC2, type 2 innate lymphoid cell; OX40L, OX40 ligand; Th, T helper; TJ, tight junction.

Figure 5

Different components of the skin barrier affected by type 2 inflammation (mainly IL-4 and IL-13). AMP, antimicrobial peptide; NMF, natural moisturizing factor.

Figure 6

Histologic changes observed with dupilumab treatment. Lesional skin samples taken from AD subjects before and 16 weeks after treatment with placebo or dupilumab (300 mg subcutaneously every 2 weeks) were stained with H&E. These two representative cases are notable for epidermal hyperplasia, spongiosis with elongated rete ridges, and a disordered basket-weave pattern to the SC layers in the placebo (baseline and 16 weeks) and dupilumab (baseline) images. After dupilumab treatment (16 weeks), the epidermis is no longer hyperplastic or spongiotic, rete ridges have normalized, and the SC is compact. In addition, these changes are seen in the context of reduced inflammatory perivascular infiltrates. Images were provided with permission from Guttman-Yassky et al. (2019a), courtesy of Emma Guttman-Yassky, Center for Excellence in Eczema, Department of Dermatology, Icahn School of Medicine at Mount Sinai (New York, NY). AD, atopic dermatitis; SC, stratum corneum.