Hypoxia induces production of citrullinated proteins in human fibroblast-like synoviocytes through regulating HIF1 alpha
Hypoxia induces production of citrullinated proteins in human fibroblast-like synoviocytes through regulating HIF1 alpha
复制标题
缺氧通过调节 HIF1 α 诱导人成纤维样滑膜细胞产生瓜氨酸蛋白
DOI：
10.1111/sji.12654
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发表时间：
2018
影响因子：
3.7
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Yu R.;Li C.;Sun L.;Jian L.;Ma Z.;Zhao J.;Liu X.;Zhao J;Liu X
缺氧是一系列疾病的显著微环境特征，包括癌症、类风湿性关节炎(RA)、动脉粥样硬化、炎症性肠病(IBD)、感染和肥胖。低氧通过调节低氧诱导因子1α(HIF1α)促进成纤维细胞样滑膜细胞的生物学功能。类风湿性关节炎中蛋白瓜氨酸化的失调促使产生针对瓜氨酸化蛋白的抗体，瓜氨酸化蛋白是类风湿性关节炎的一个高度特异的生物标志物。然而，促进类风湿关节炎瓜氨酸化的机制尚未完全阐明。在这项研究中，我们研究了类风湿滑膜中发现的病理生理缺氧是否调节了人成纤维样滑膜细胞(HFLS)的瓜氨酸化。在这里，我们发现在低氧条件下，HFLS中的PAD2和瓜氨酸蛋白表达增加。此外，用HIF1αsiRNA敲除HIF1α可改善PAD2和瓜氨酸蛋白的表达。总之，这项研究提供了一种新的机制，参与了瓜氨酸蛋白的产生：低氧促进了高脂蛋白的瓜氨酸化和PAD的产生。同时，我们还提出了一种新的缺氧参与类风湿关节炎发病机制。本研究加深了我们对缺氧在类风湿关节炎发病机制中作用的认识，为类风湿关节炎的治疗提供了一种潜在的治疗策略。
Hypoxia is a prominent microenvironment feature in a range of disorders including cancer, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel disease (IBD), infection and obesity. Hypoxia promotes biological functions of fibroblast‐like synoviocytes via regulating hypoxia‐inducible factor 1α (HIF1α). Dysregulated protein citrullination in RA drives the production of antibodies to citrullinated proteins, a highly specific biomarker of RA. However, the mechanisms promoting citrullination in RA are not yet fully elucidated. In this study, we investigated whether pathophysiological hypoxia as found in the rheumatoid synovium modulates the citrullination in human fibroblast‐like synoviocytes (HFLS). Here, we found that peptidylarginine deiminase 2 (PAD2) and citrullinated proteins were increased in HFLS after exposure to hypoxia. Moreover, knocking down HIF1α by HIF1α siRNA ameliorated the expression of PAD2 and citrullinated proteins. Collectively, this study provides a new mechanism involved in generating citrullinated proteins: hypoxia promotes citrullination and PAD production in HFLS. Concurrently, we also proposed a novel hypoxia involved mechanism in RA pathogenesis. This study deepens our understanding of the role of hypoxia in the pathogenesis of RA and provides a potential therapeutic strategy for RA.