Systemic sclerosis (SSc) is an inflammatory fibrotic disease characterized by an excessive extracellular matrix deposition in the skin and internal organs. One fibrotic key event remains the fibroblast-to-myofibroblast differentiation that is controlled by a combination of mechanical and soluble factors, such as transforming growth factor-β1 (TGF-β1) and interleukin-1β (IL-1β). One important myofibroblast biomarker is human xylosyltransferase-I (XT-I), the initial enzyme in proteoglycan biosynthesis. Increased serum XT activity was quantified in SSc, but the underlying cellular mechanisms remain elusive. This study aims to determine the cellular basis of XT-I induction in SSc by using a myofibroblast cell culture model with SSc fibroblasts (SScF) and healthy control fibroblasts. We found that SScF exhibit a higher extracellular XT-I activity compared to control fibroblasts. This increased XT-I activity in SScF was demonstrated to be mediated by an enhanced autocrine TGF-β signaling. Upon IL-1β treatment, SScF showed an increased mRNA expression level of XT-I and TGF-β receptor II (TGFBR2), while healthy control fibroblasts did not, pointing towards an involvement of IL-1β in the cytokine-mediated XT-I induction. Performing microRNA (miRNA) inhibition experiments in the presence of TGF-β1, we showed that the pro-fibrotic effect of IL-1β may be mediated by a miRNA-21/TGF-β receptor II axis, enhancing the autocrine TGF-β signaling in SScF. Taken together, this study improves the mechanistic understanding of fibrotic XT-I induction in SSc by identifying a hitherto unknown IL-1β-mediated miRNA-21/TGFBR2 regulation contributing to the enhanced XYLT1 expression and XT-I activity in SScF.
Keywords: Fibrosis; Interleukin-1β; Systemic sclerosis; TGF-β receptor II; Xylosyltransferase-I; microRNA-21.
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