Yu R, Li C, Sun L, Jian L, Ma Z, Zhao J, Liu X
Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China.
Scand J Immunol. 2018 Apr;87(4):e12654. doi: 10.1111/sji.12654.
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.
缺氧是一系列疾病（包括癌症、类风湿性关节炎（RA）、动脉粥样硬化、炎症性肠病（IBD）、感染和肥胖症）中显著的微环境特征。缺氧通过调节缺氧诱导因子1α（HIF1α）促进成纤维细胞样滑膜细胞的生物学功能。RA中蛋白质瓜氨酸化失调会导致抗瓜氨酸化蛋白抗体的产生，这是RA的一种高度特异性生物标志物。然而，RA中促进瓜氨酸化的机制尚未完全阐明。在本研究中，我们调查了类风湿滑膜中发现的病理生理缺氧是否会调节人成纤维细胞样滑膜细胞（HFLS）中的瓜氨酸化。在此，我们发现暴露于缺氧环境后，HFLS中的肽基精氨酸脱亚氨酶2（PAD2）和瓜氨酸化蛋白增加。此外，用HIF1α siRNA敲低HIF1α可改善PAD2和瓜氨酸化蛋白的表达。总体而言，本研究提供了一种参与生成瓜氨酸化蛋白的新机制：缺氧促进HFLS中的瓜氨酸化和PAD产生。同时，我们还提出了一种RA发病机制中涉及的新的缺氧相关机制。本研究加深了我们对缺氧在RA发病机制中作用的理解，并为RA提供了一种潜在的治疗策略。
