Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
Theranostics. 2021 Jan 1;11(3):1446-1457. doi: 10.7150/thno.47860. eCollection 2021.
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. 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. 3 mice were introduced to assess the influence of NLRP3 on γδT17 cell activation in RA. 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 mice verified that the NLRP3 inflammasome mediated the effect of TOF on γδT17 cell activation. 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.
托法替尼（TOF）是一种用于治疗类风湿关节炎（RA）的 Janus 激酶（JAK）抑制剂，但作用机制尚不清楚。在这项研究中，我们研究了 TOF 对 RA 中γδ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（NLRP3）炎症小体在这一过程中的作用。我们使用酶联免疫吸附试验（ELISA）检测 RA 患者在接受 TOF 治疗前后血清中炎症因子的水平。构建胶原诱导性关节炎（CIA）模型，以研究 TOF 对关节炎症状、γδTreg/γδT17 细胞平衡和 NLRP3 炎症小体的影响。我们使用骨髓来源的巨噬细胞（BMDMs）研究 TOF 对 NLRP3 炎症小体激活的影响。引入 3 只小鼠评估 NLRP3 对 RA 中 γδT17 细胞激活的影响。TOF 治疗降低了 RA 患者与 γδT17 细胞相关的细胞因子白细胞介素-17（IL-17）的水平。此外，TOF 干预 CIA 模型可减轻关节炎症和损伤，重新平衡 γδTreg/γδT17 细胞比例，并抑制引流淋巴结和关节炎关节中过度的 NLRP3 炎症小体激活。BMDM 干预实验表明，TOF 通过下调 NLRP3 降低了分泌的 IL-1β水平。此外，使用 小鼠的实验验证了 NLRP3 炎症小体介导了 TOF 对 γδT17 细胞激活的作用。恢复 γδTreg/γδT17 细胞平衡是 TOF 缓解 RA 的一种新机制。同时，NLRP3 在 TOF 介导的 γδT17 细胞激活过程中发挥关键作用。
