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IL-25 participates in keratinocyte-driven dermal matrix turnover and is reduced in Systemic Sclerosis epidermis

ABSTRACT: Aberrant deposition of extracellular matrix (ECM) resulting in dermal fibrosis is a hallmark of systemic sclerosis (SSc). Evidence suggests that dysfunctional SSc keratinocytes may contribute to fibrosis by altering dermal homeostasis. Whether interleukin-25 (IL-25), an IL-17 family member involved in epithelial/mesenchymal/immune cell interplay takes part in skin fibrosis is unknown. Here we address the role of IL-25 in SSc skin fibrosis. Compared to healthy donor (HD), in SSc and scleroderma-like disorders the epidermis expressed significantly lower levels of IL-25. In epidermal equivalents, IL-25 regulated several molecular pathways related to wound healing and ECM remodeling. Compared to control conditioned medium (CM), the CM from IL-25-primed keratinocytes enhanced the production by fibroblasts of matrix metalloproteinase-1 (MMP-1), IL-6, IL-8 (p< 0.05), but not of type-I collagen (Col-I ) nor fibronectin. However, IL- 25 significantly reduced the production of Col-I when applied directly to fibroblasts. The activation of keratinocytes by IL-25 was receptor-dependent and evident after a very short incubation time (10 min), largely mediated by IL-1, suggesting enhanced and specific release of preformed mediators. These results show that IL-25 participates to skin homeostasis and its decreased expression in SSc may contribute to skin fibrosis by favoring ECM deposition over degradation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168312 | GEO | 2022/03/31

REPOSITORIES: GEO

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Dysfunctional epidermis increases dermis inflammation in systemic sclerosis: results from a novel epidermal equivalent engineered from SSc keratinocytes.

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Dissociating fibrosis from inflammation in systemic sclerosis – the case of interleukin-17A

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2019-11-01 | GSE131615 | GEO

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Project description:Systemic sclerosis (SSc) is a chronic, heterogenous multisystem connective tissue disease characterized by vascular injury, autoimmunity, and organ fibrosis. Epigenetic modification is thought to be important in the onset and progression of SSc. SOX (SRY-related HMG box) 11 is a transcription factor playing several important roles in organ development in embryos. We have previously shown that dermal fibroblasts derived from SSc patients showed constitutive, high expression of SOX11 and a positive loop formed by SOX11 and periostin in fibroblasts upregulates the TGF- signals, leading to skin fibrosis. However, the mechanism of the aberrant high expression of SOX11 remain unknown in the pathogenesis of SSc. In this study, we found that SOX11 high expression is associated with presence of activating histone marks (H3K27Ac) in SSc dermal fibroblasts. In contrast, normal fibroblasts express low level of SOX11 associated with silencing histone marks H3K27me3. Moreover, using the miRNA microarray method, we identified some miRNAs downregulated in SSc dermal fibroblasts and target SOX11 and overexpression of these miRNAs significantly repressed the expression of SOX11 in SSc dermal fibroblasts. Our findings, taken together, show that epigenetic activation of SOX11 in systemic sclerosis fibroblasts upregulates the SOX11 expression, leading to skin fibrosis.

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