Mechanisms regulating the loss of Tregs in HUPO mice that develop spontaneous inflammatory arthritis.
Mechanisms regulating the loss of Tregs in HUPO mice that develop spontaneous inflammatory arthritis.
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DOI：
10.1016/j.isci.2023.106734
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发表时间：
2023-05-19
期刊：
影响因子：
5.8
通讯作者：
Pope, Richard M.
中科院分区：
文献类型：
--
作者：
Huang, Qi-Quan;Hang, Yiwei;Doyle, Renee;Mao, Qinwen;Fang, Deyu;Pope, Richard M.
T 调节细胞 (Treg) 是包括类风湿性关节炎 (RA) 在内的许多自身免疫性疾病的潜在治疗靶点。人们对于在 RA 等慢性炎症性疾病中维持 Tregs 的机制知之甚少。我们采用了 RA 小鼠模型，其中 CD11c+ 细胞中 Flice 样抑制蛋白缺失后，CD11c-FLIP-KO (HUPO) 小鼠出现自发性、进行性、糜烂性关节炎，Treg 细胞减少，Treg 细胞的过继转移可改善关节炎。 HUPO 胸腺 Treg 发育正常，但外周 Treg Foxp3 由于树突状细胞和白细胞介素 2 (IL-2) 的减少而减少。在慢性炎症关节炎期间，Tregs 无法维持 Foxp3，导致非凋亡细胞死亡并转化为 CD4+CD25+Foxp3- 细胞。 IL-2 治疗可增加 Tregs 并改善关节炎。总之，慢性炎症环境中树突状细胞和 IL-2 的减少导致 Treg 不稳定，促进 HUPO 关节炎进展，并提出了 RA 的治疗方法。 CD11c+ 细胞（HUPO 小鼠）中的 FLIP 缺失导致自发性糜烂性关节炎 在 Treg 丧失之前 Foxp3 表达减少 HUPO Treg 不稳定是由 DC、IL-2 和慢性炎症减少介导的 IL-2 复合物治疗可增加 Tregs 并改善 HUPO 关节炎
T regulatory cells (Tregs) are a potential therapeutic target in many autoimmune diseases including rheumatoid arthritis (RA). The mechanisms responsible for the maintenance of Tregs in chronic inflammatory conditions such as RA are poorly understood. We employed our mouse model of RA in which, the following deletion of Flice-like inhibitory protein in CD11c+ cells, CD11c-FLIP-KO (HUPO) mice develop spontaneous, progressive, erosive arthritis, with reduced Tregs, and the adoptive transfer of Tregs ameliorates the arthritis. HUPO thymic Treg development was normal, but peripheral of Treg Foxp3 was diminished mediated by reduction of dendritic cells and interleukin-2 (IL-2). During chronic inflammatory arthritis Tregs fail to maintain Foxp3, leading to non-apoptotic cell death and conversion to CD4+CD25+Foxp3- cells. Treatment with IL-2 increased Tregs and ameliorated the arthritis. In summary, reduced dendritic cells and IL-2 in the milieu of chronic inflammation, contribute to Treg instability, promoting HUPO arthritis progression, and suggesting a therapeutic approach in RA. FLIP deletion in CD11c+ cells (HUPO mice) results in spontaneous, erosive arthritis Reduced Foxp3 expression occurs before Treg loss HUPO Treg instability is mediated by reduced DCs, IL-2, and chronic inflammation IL-2 complex treatment increases Tregs and ameliorates HUPO arthritis Immunology
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影响因子：
8.8
作者：
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DOI：
10.1073/pnas.1524660113
发表时间：
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通讯作者：
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