Transcriptomic Analysis of Healthy and Atopic Dermatitis Samples Reveals the Role of IL-37 in Human Skin

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects up to one in five children and millions of adults in developed countries. Clinically, AD skin lesions manifest as subacute and/or chronic lichenified eczematous plaques, which are often intensely pruritic and prone to secondary bacterial and viral infections. Despite the emergence of novel therapeutic agents, treatment options and outcomes for AD remain suboptimal. An improved understanding of AD pathogenesis may help improve patient outcomes. Dysregulated T h 2-polarized skin inflammation and impaired skin barrier function interact to drive AD pathogenesis; however, much remains to be understood about the molecular mechanisms underlying this interplay. The current study used published clinical trial datasets to define a skin-related AD gene signature. This meta-analysis revealed significant reductions in IL1F7 transcripts (encodes IL-37) in AD patient samples. Reduced IL1F7 correlated with lower transcripts for key skin barrier function genes in the epidermal differentiation complex. Immunohistochemical analysis of normal (healthy) human skin specimens and an in vitro three-dimensional human skin model localized IL-37 protein to the epidermis. In comparison with normal human skin, IL-37 levels were decreased in AD patient skin. Addition of T h 2 cytokines to the aforementioned in vitro three-dimensional skin model recapitulates key aspects of AD skin and was sufficient to reduce epidermal IL-37 levels. Image analysis also indicated close relationship between epidermal IL-37 and skin epidermal differentiation complex proteins. These findings suggest IL-37 is intimately linked to normal keratinocyte differentiation and barrier function and implicates IL-37 as a potential biomarker and therapeutic target for AD. ImmunoHorizons, 2021, 5: 830-843.

Regulation of immune response genes in the skin of allergic and clinically tolerant individuals exposed to p‐phenylenediamine

“…47 It has been suggested that IL-37 plays a role in keeping an intact skin barrier and that Th2 cytokines down-regulate IL-37 expression. 48 In accordance, we found strongly down-regulated IL37 levels associated with high levels of Th2 cytokines in individuals with severe allergy. In a previous study, we found strongly downregulated skin barrier proteins in the same individuals with severe allergy to PPD.…”

Cytokines and Epidermal Lipid Abnormalities in Atopic Dermatitis: A Systematic Review

“…The processing and incorporation of ceramides, fatty This systemic review found studies involving cytokines IL-4, IL-13, IL-31, IL-17, IL-31, IFN-γ, TNF-α, and GM-CSF for their effects on epidermal lipids in AD skin. In addition, it highlights the lack of studies investigating the effect on epidermal lipids of additional cytokines dysregulated in AD, such as TSLP, IL-22, IL-25, IL-33, IL-9, and IL-37 [25,49]. Most of the studies focused on cytokine analysis in AD skin have employed bulk or single-cell RNA sequencing, tissue-level proteomics, immunohistochemistry, ELISA, and Western blotting and have utilized skin biopsies or tape strips.…”

“…T H 2 cells are mainly responsible for the secretion of IL-4, IL-5, IL-13, and IL-31 cytokines in AD [5]. It is clear that the combination of T H 2 cytokines IL-4, IL-13, and IL-31, when present in the skin, induces inflammation and AD-like phenotype [48,49]. Experiments on full-thickness human skin equivalents to determine whether skin inflammation affects epidermal lipid biosynthesis showed that treatment with a cocktail of IL-4, IL-13, and IL-31 resulted in significantly lower mRNA levels of genes encoding ELOVL1, acid SMase and β-GCase, which are involved in lipid chain elongation and ceramide synthesis, suggesting a direct role of T H 2 cytokines on lipid biosynthesis and alterations in AD [33].…”

Interleukin‐1 family cytokines at the crossroads of microbiome regulation in barrier health and disease

“…The functional role of the IL-18 subfamily member, IL-37 in the context of dermal inflammation remains relatively ill-defined. Several recent studies have demonstrated that IL-37 expression is decreased in lesional skin from psoriasis, AD, and Hidradenitis suppurativa (HS) patients [164][165][166] suggesting that loss of its immunosuppressive activity may be important. In addition, several studies have suggested that IL-37 may play an important role in regulating the expression of epidermal differentiation complex proteins and in maintaining a healthy skin barrier [165,167].…”

“…Several recent studies have demonstrated that IL-37 expression is decreased in lesional skin from psoriasis, AD, and Hidradenitis suppurativa (HS) patients [164][165][166] suggesting that loss of its immunosuppressive activity may be important. In addition, several studies have suggested that IL-37 may play an important role in regulating the expression of epidermal differentiation complex proteins and in maintaining a healthy skin barrier [165,167]. In contrast, it has also been suggested that specific proteolytic processing leads to the expression of a proinflammatory form of IL-37 which can elicit psoriatic-like inflammatory responses in the skin, at least in part through engaging the IL-36R.…”