Tofacitinib restores the balance of γδTreg/γδT17 cells in rheumatoid arthritis by inhibiting the NLRP3 inflammasome.
Tofacitinib restores the balance of γδTreg/γδT17 cells in rheumatoid arthritis by inhibiting the NLRP3 inflammasome.
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Tofacitinib 通过抑制 NLRP3 炎性体恢复类风湿性关节炎中 γδTreg/γδT17 细胞的平衡
作者：
Yang X;Zhan N;Jin Y;Ling H;Xiao C;Xie Z;Zhong H;Yu X;Tang R;Ma J;Guan J;Yin G;Wu G;Lu L;Wang J
目的：托法替尼（TOF）是一种用于治疗类风湿性关节炎（RA）的Janus激酶（JAK）抑制剂，但其作用机制尚不清楚。在这项研究中，我们研究了TOF对RA中γ δ调节性T细胞（γδTreg）/γδT17细胞平衡的影响以及核苷酸结合域（NOD）样受体蛋白3（NLRP 3）炎性体在此过程中的作用。研究方法：采用酶联免疫吸附试验（ELISA）检测RA患者TOF治疗前后血清中炎性因子水平。建立胶原诱导性关节炎（CIA）模型，观察TOF对CIA大鼠关节炎症状、γδTreg/γδT17细胞平衡和NLRP 3炎性小体的影响。我们使用骨髓来源的巨噬细胞（BMDM）来研究TOF对NLRP 3炎性小体活化的影响。引入NLRP 3-/-小鼠以评估NLRP 3对RA中γδT17细胞活化的影响。结果：TOF治疗可降低RA患者γδT17细胞相关细胞因子IL-17的水平。此外，CIA模型中的TOF干预减少了关节炎症和损伤，重新平衡了γδTreg/γδT17细胞比率，并抑制了引流淋巴结和关节炎关节中过度的NLRP 3炎性小体活化。BMDM干预实验表明TOF通过下调NLRP 3降低IL-1β的分泌水平。此外，使用Nlrp 3-/-小鼠的实验证实了NLRP 3炎性体介导TOF对γδT17细胞活化的作用。结论：γδTreg/γδT17细胞平衡的恢复是TOF减轻RA的新机制。同时，NLRP 3在TOF介导的γδT17细胞活化过程中起关键作用。
Objective: Tofacitinib (TOF) is a Janus kinase (JAK) inhibitor used in the treatment of rheumatoid arthritis (RA), but the mechanism of its action remains unclear. In this study, we investigated the influence of TOF on gamma delta regulatory T-cell (γδTreg)/γδT17 cell balance in RA and the role of the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in this process. Methods: We detected levels of inflammatory factors in the serum of RA patients before and after administration of TOF using an enzyme-linked immunosorbent assay (ELISA). A collagen-induced arthritis (CIA) model was constructed to investigate the effect of TOF on arthritis symptoms, γδTreg/γδT17 cell balance and the NLRP3 inflammasome. We used bone marrow-derived macrophages (BMDMs) to study the effect of TOF on NLRP3 inflammasome activation. Nlrp3-/- mice were introduced to assess the influence of NLRP3 on γδT17 cell activation in RA. Results: TOF treatment decreased levels of γδT17 cell-related cytokine interleukin-17 (IL-17) in RA patients. In addition, TOF intervention in the CIA model reduced joint inflammation and damage, rebalanced the γδTreg/γδT17 cell ratio and inhibited excessive NLRP3 inflammasome activation in draining lymph nodes and arthritic joints. BMDM intervention experiments demonstrated that TOF decreased the level of secreted IL-1β via downregulation of NLRP3. Furthermore, experiments using Nlrp3-/- mice verified that the NLRP3 inflammasome mediated the effect of TOF on γδT17 cell activation. Conclusions: Recovery of γδTreg/γδT17 cell balance was a novel mechanism by which TOF alleviated RA. Meanwhile, NLRP3 played a pivotal role in the process of TOF-mediated γδT17 cell activation.
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