The Contribution of LIGHT (TNFSF14) to the Development of Systemic Sclerosis by Modulating IL-6 and T Helper Type 1 Chemokine Expression in Dermal Fibroblasts.
The Contribution of LIGHT (TNFSF14) to the Development of Systemic Sclerosis by Modulating IL-6 and T Helper Type 1 Chemokine Expression in Dermal Fibroblasts.
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光 (TNFSF14) 通过调节真皮成纤维细胞中 IL-6 和 T 辅助细胞 1 型趋化因子表达对系统性硬化症的发展的贡献。
DOI：
10.1016/j.jid.2021.10.028
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Asano Y.
中科院分区：
文献类型：
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作者：
Ikawa T;Ichimura Y;Miyagawa T;Fukui Y;Toyama S;Omatsu J;Awaji K;Norimatsu Y;Watanabe Y;Yoshizaki A;Sato S;Asano Y.
系统性硬化症（SSc）是一种导致多器官纤维化的自身免疫性和血管性疾病，其中IL-6和T辅助细胞（Th）2/Th 17细胞因子充当危重疾病驱动因素。LIGHT是一种促炎细胞因子，可促进肺成纤维细胞中IL-6的产生和IFN-γ刺激的真皮成纤维细胞（DF）中Th 1趋化因子的表达。在这项研究中，我们使用临床样本和动物模型研究了LIGHT对SSc发展的潜在贡献。在SSc参与的皮肤中，LIGHT在炎性细胞中上调，而LIGHT的受体疱疹病毒进入介质（HVEM）在DF中下调。在博来霉素处理的小鼠中再现了LIGHT和HVEM的类似表达谱。转录因子FLI 1与HVEM启动子结合，FLI 1小干扰RNA抑制正常DF中HVEM的表达。在SSc DF中，LIGHT显著增加IL-6的产生，而IFN-γ/LIGHT依赖性Th 1趋化因子的诱导与正常DF相比减少。重要的是，LIGHT小干扰RNA显著减弱博莱霉素诱导的皮肤纤维化，弥漫性皮肤SSc患者血清LIGHT水平升高，与反映皮肤和肺纤维化的临床参数呈正相关。总之，这些结果表明，DF对LIGHT的反应改变，即IL-6产生增加和Th 1趋化因子表达减少，有助于SSc中皮肤纤维化的发展。
Systemic sclerosis (SSc) is an autoimmune and vascular disease resulting in multiple organ fibrosis, in which IL-6 and T helper (Th)2/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 (DFs) stimulated with 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 upregulated in inflammatory cells, whereas herpesvirus entry mediator (HVEM), a receptor of LIGHT, was downregulated in DFs. Similar expression profiles of LIGHT and HVEM were reproduced in bleomycin-treated mice. Transcription factor FLI1 bound to theHVEMpromoter, andFLI1small interfering RNA suppressed HVEM expression in normal DFs. In SSc DFs, LIGHT significantly increased IL-6 production, whereas IFN-γ/LIGHT-dependent Th1 chemokine induction was decreased compared with that in normal DFs. Importantly,LIGHTsmall interfering RNA 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 DFs to LIGHT, namely increased IL-6 production and decreased Th1 chemokine expression, contributes to the development of skin fibrosis in SSc.