EZH2 deficiency attenuates Treg differentiation in rheumatoid arthritis
EZH2 deficiency attenuates Treg differentiation in rheumatoid arthritis
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EZH2 缺陷会减弱类风湿关节炎中的 Treg 分化
DOI：
10.1016/j.jaut.2020.102404
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发表时间：
2020
影响因子：
12.8
通讯作者：
Zhang Xuan
中科院分区：
文献类型：
--
作者：
Xiao Xin-yue;Li Yue-ting;Jiang Xu;Ji Xin;Lu Xin;Yang Bo;Wu Li-jun;Wang Xiao-han;Guo Jing-bo;Zhao Li-dan;Fei Yun-yun;Yang Hua-xia;Zhang Wen;Zhang Feng-chun;Tang Fu-lin;Zhang Jian-min;He Wei;Chen Hua;Zhang Xuan
染色质修饰增强子zeste同源物2（EZH 2）甲基化组蛋白H3（H3 K27）的赖氨酸27并调节T细胞分化。然而，EZH 2在类风湿性关节炎（RA）发病机制中的潜在作用仍然难以捉摸。我们分析了EZH 2在来自活动性初治RA患者和健康对照（HC）的PBMC、CD 4 +T细胞、CD 19 +B细胞和CD 14+单核细胞中的表达。我们还使用EZH 2抑制剂GSK 126抑制EZH 2表达，并测量CD 4 +T细胞分化、增殖和凋亡。我们进一步研究了EZH 2抑制的CD 4 +T细胞中的TGFβ-SMAD和RUNX 1信号通路。最后，我们探讨了RA滑液和成纤维细胞样滑膜细胞（FLS）通过中和关键的促炎细胞因子对EZH 2的调节机制。EZH 2在RA患者PBMC和CD 4 +T细胞中的表达低于HC。EZH 2抑制抑制调节性T细胞（TcB）分化和FOXP 3转录，下调RUNX 1和上调SMAD 7在CD 4 +T细胞中的表达。RA滑液和成纤维细胞样滑膜细胞抑制CD 4 +T细胞EZH 2的表达，抗IL-17抗体部分中和了这种抑制作用。综上所述，RA患者CD 4 +T细胞中的EZH 2被减弱，其通过下调CD 4 +T细胞中的RUNX 1和上调SMAD 7来抑制FOXP 3转录，并最终抑制T细胞分化。RA滑液中IL 17可能促进CD 4 +T细胞EZH 2表达下调。CD 4 +T细胞中EZH 2的缺陷可能导致RA中Treg缺陷。
The chromatin modifier enhancer of zeste homolog 2 (EZH2) methylates lysine 27 of histone H3 (H3K27) and regulates T cell differentiation. However, the potential role of EZH2 in the pathogenesis of rheumatoid arthritis (RA) remains elusive. We analyzed EZH2 expression in PBMC, CD4+T cells, CD19+B cell, and CD14+monocytes from active treatment-naïve RA patients and healthy controls (HC). We also suppressed EZH2 expression using EZH2 inhibitor GSK126 and measured CD4+T cell differentiation, proliferation and apoptosis. We further examined TGFβ-SMAD and RUNX1 signaling pathways in EZH2-suppressed CD4+T cells. Finally, we explored the regulation mechanism of EZH2 by RA synovial fluid and fibroblast-like synoviocyte (FLS) by neutralizing key proinflammatory cytokines. EZH2 expression is lower in PBMC and CD4+T cells from RA patients than those from HC. EZH2 inhibition suppressed regulatory T cells (Tregs) differentiation and FOXP3 transcription, and downregulated RUNX1 and upregulated SMAD7 expression in CD4+T cells. RA synovial fluid and fibroblast-like synoviocytes suppressed EZH2 expression in CD4+T cells, which was partially neutralized byanti-IL17 antibody. Taken together, EZH2 in CD4+T cells from RA patients was attenuated, which suppressed FOXP3 transcription through downregulating RUNX1 and upregulating SMAD7 in CD4+T cells, and ultimately suppressed Tregs differentiation. IL17 in RA synovial fluid might promote downregulation of EZH2 in CD4+T cells. Defective EZH2 in CD4+T cells might contribute to Treg deficiency in RA.