Wang Meiqi, Huang Xue, Shu Jia, Li Hongxi, Yang Tao, Li Na, Yang Peizeng
Department of Ophthalmology, Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, The First Affiliated Hospital of Zhengzhou University, Henan International, Henan Province Eye Hospital, Zhengzhou, P.R. China.
Chongqing Key Laboratory of Ophthalmology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, P.R. China.
Inflammation. 2024 Sep 29. doi: 10.1007/s10753-024-02149-5.
Irisin, proteolytically cleaved from Fndc5 protein, has been identified as an exercise-related hormone. Here, we investigated the irisin levels in aqueous humor and its involvement in the pathogenesis of uveitis. The results revealed that the irisin level in the aqueous humor was significantly decreased in Vogt-Koyanagi-Harada (VKH), and Behcet uveitis (BU) patients, and was negatively correlated with TNF-α in BU patients. Exogenous supplementation of irisin alleviated scores of experimental autoimmune uveitis (EAU) clinically and pathologically and suppressed the proportion of Th1 and Th17 cells in spleen. Fndc5 EAU mice exhibited more severe inflammatory manifestations with increased microglial activation in the retina. Irisin could mitigate M1 microglia and promote M2 microglia polarization. RNA sequencing of the retina showed that HIF-1α pathway was significantly enriched in Fndc5 EAU mice. HIF-1α pathway inhibitor significantly rescued EAU severity, associated with a decreased M1 microglial polarization in the retina of Fndc5 mice. In conclusion, we highlighted that irisin could alleviate uveitis by inhibiting Th1 and Th17 cells and reducing M1 microglial polarization via HIF-1α pathway.
鸢尾素是从Fndc5蛋白经蛋白水解切割而来，已被鉴定为一种与运动相关的激素。在此，我们研究了房水中的鸢尾素水平及其在葡萄膜炎发病机制中的作用。结果显示，伏格特-小柳-原田（VKH）病和白塞氏葡萄膜炎（BU）患者房水中的鸢尾素水平显著降低，且在BU患者中与肿瘤坏死因子-α呈负相关。外源性补充鸢尾素在临床和病理上减轻了实验性自身免疫性葡萄膜炎（EAU）的评分，并抑制了脾脏中Th1和Th17细胞的比例。Fndc5基因敲除的EAU小鼠表现出更严重的炎症表现，视网膜中的小胶质细胞激活增加。鸢尾素可减轻M1型小胶质细胞并促进M2型小胶质细胞极化。视网膜的RNA测序显示，HIF-1α通路在Fndc5基因敲除的EAU小鼠中显著富集。HIF-1α通路抑制剂显著改善了EAU的严重程度，这与Fndc5基因敲除小鼠视网膜中M1型小胶质细胞极化的减少有关。总之，我们强调鸢尾素可通过抑制Th1和Th17细胞并通过HIF-1α通路减少M1型小胶质细胞极化来减轻葡萄膜炎。
