Session Type: Abstract Submissions (ACR)
Background/Purpose: Systemic sclerosis (SSc) is a multisystem autoimmune disorder characterized by vascular injuries and fibrosis development. In SSc lesional skin, transcription factor Friend leukemia virus integration 1 (Fli1) is constitutively down-regulated in various cell types, especially by an epigenetic mechanism in dermal fibroblasts, and Fli1 deficiency is deeply related to the pathogenesis of SSc. In particular, endothelial Fli1 deficiency reproduces the histological and functional abnormalities characteristic of SSc vasculopathy in vivo. Recently, adipocytokines have drawn much attention in the research field of various autoimmune diseases. Chemerin is a member of adipocytokines with a chemoattractant effect and a pro-angiogenic property, and has been shown to have pivotal roles in the pathogenesis of various autoimmune diseases. To elucidate the role of chemerin in the developmental process of SSc, we investigated the expression levels of chemerin in SSc lesional skin and the mechanism underlying its altered expression, and the clinical correlation of serum chemerin levels in SSc patients.
Methods: Expression of chemerin and its receptor, ChemR23, was evaluated by immunostaining and/or quantitative reverse transcription-real time PCR in human and/or murine skin. The mechanisms regulating chemerin expression in dermal fibroblasts and endothelial cells were examined by gene silencing technique and chromatin immunoprecipitation. Serum chemerin levels were determined by enzyme-linked immunosorbent assay in 64 SSc and 19 healthy subjects.
Results: In SSc lesional skin, chemerin was up-regulated in small blood vessels, down-regulated in activated fibroblasts surrounded with thickened collagen bundles, but not altered in inflammatory cells, while ChemR23 expression was comparable in various cell types. Chemerin expression was also markedly decreased in dermal fibroblasts of bleomycin-treated SSc model mice. Importantly, the decreased expression of chemerin was significantly reversed by blocking autocrine transforming growth factor (TGF)-β signaling with TGF-β1 antisense oligonucleotide in cultured SSc dermal fibroblast. As for endothelial cells, gene silencing of Fli1, which directly bound to the chemerin promoter, induced chemerin expression in human dermal microvascular endothelial cells and Fli1+/- mice exhibited elevated chemerin expression in dermal blood vessels. Regarding the correlation of serum chemerin levels with clinical features in SSc patients, serum chemerin levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction while, in SSc patients with normal renal function, patients with digital ulcers had higher serum chemerin levels than those without.
Conclusion: Chemerin is down-regulated in SSc dermal fibroblasts by autocrine TGF-β, while up-regulated in SSc dermal blood vessels through endothelial Fli1 deficiency. In SSc, dysregulated chemerin/ChemR23 axis by endothelial Fli1 deficiency may contribute to the development of SSc vasculopathy through altering angiogenic/angiostatic signaling pathways.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/increased-expression-of-chemerin-in-endothelial-cells-due-to-fli1-deficiency-may-contribute-to-the-development-of-digital-ulcers-in-systemic-sclerosis/