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The contribution of LIGHT to the development of systemic sclerosis by modulating IL-6 and Th1 chemokine expression in dermal fibroblasts

Published:November 25, 2021DOI:https://doi.org/10.1016/j.jid.2021.10.028

      Abstract

      Systemic sclerosis (SSc) is an autoimmune and vascular disease resulting in multiple organ fibrosis, in which IL-6 and Th2/Th17 cytokines serve as critical disease drivers. LIGHT is a proinflammatory cytokine, promoting IL-6 production in lung fibroblasts and Th1 chemokine expression in dermal fibroblasts stimulated with interferon-γ (IFN-γ). In this study we investigated the potential contribution of LIGHT to SSc development using clinical samples and animal models. In SSc-involved skin, LIGHT was up-regulated in inflammatory cells, while HVEM, a receptor of LIGHT, was down-regulated in dermal fibroblasts. Similar expression profiles of LIGHT and HVEM were reproduced in bleomycin-treated mice. Transcription factor FLI1 bound to the HVEM promoter and FLI1 siRNA suppressed HVEM expression in normal dermal fibroblasts. In SSc dermal fibroblasts, LIGHT significantly increased IL-6 production, while IFN-γ/LIGHT-dependent Th1 chemokine induction was decreased compared with normal dermal fibroblasts. Importantly, Light siRNA significantly attenuated bleomycin-induced skin fibrosis, and serum LIGHT levels were elevated in patients with diffuse cutaneous SSc and positively correlated with clinical parameters reflecting skin and pulmonary fibrosis. Taken together, these results suggest that altered response of dermal fibroblasts to LIGHT, namely increased IL-6 production and decreased Th1 chemokine expression, contributes to the development of skin fibrosis in SSc.

      Abbreviations:

      BLM (bleomycin), dcSSc (diffuse cutaneous systemic sclerosis), DFs (dermal fibroblasts), ECs (endothelial cells), FLI1 (Friend leukemia virus integration 1), HVEM (herpesvirus entry mediator), ILD (interstitial lung disease), LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes), LTβR (lymphotoxin β receptor), mRSS (modified Rodnan total skin thickness score), NDFs (normal dermal fibroblasts), PBS (phosphate buffered saline), qRT-PCR (quantitative reverse transcription PCR), SCR (non-silencing scrambled RNA), SSc (systemic sclerosis), TGF (transforming growth factor), Th (T helper), TNF (tumor necrosis factor), Tregs (regulatory T cells), TSLP (thymic stromal lymphopoietin), WT (wild-type)
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