Center for Research in Inflammatory Diseases, CRID, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
FASEB J. 2020 Aug;34(8):10907-10919. doi: 10.1096/fj.202000795R. Epub 2020 Jul 7.
Nucleotide oligomerization domain (NOD)-like receptor-12 (NLRP12) has emerged as a negative regulator of inflammation. It is well described that the Th17 cell population increases in patients with early Rheumatoid Arthritis (RA), which correlates with the disease activity. Here, we investigated the role of NLRP12 in the differentiation of Th17 cells and the development of experimental arthritis, using the antigen-induced arthritis (AIA) murine model. We found that Nlrp12 mice develop severe arthritis characterized by an exacerbated Th17-mediated inflammatory response with increases in the articular hyperalgesia, knee joint swelling, and neutrophil infiltration. Adoptive transfer of Nlrp12 cells into WT mice recapitulated the hyperinflammatory response seen in Nlrp12 mice and the treatment with anti-IL-17A neutralizing antibody abrogated arthritis development in Nlrp12 mice, suggesting that NLRP12 works as an inhibitor of Th17 cell differentiation. Indeed, Th17 cell differentiation markedly increases in Nlrp12 T cells cultured under the Th17-skewing condition. Mechanistically, we found that NLRP12 negatively regulates IL-6-induced phosphorylation of STAT3 in T cells. Finally, pharmacological inhibition of STAT3 reduced Th17 cell differentiation and abrogated hyperinflammatory arthritis observed in Nlrp12 mice. Thus, we described a novel role for NLRP12 as a checkpoint inhibitor of Th17 cell differentiation, which controls the severity of experimental arthritis.
核苷酸寡聚化结构域（NOD）样受体-12（NLRP12）已成为炎症的负调控因子。众所周知，Th17 细胞群在早期类风湿关节炎（RA）患者中增加，这与疾病活动度相关。在这里，我们使用抗原诱导关节炎（AIA）的小鼠模型研究了 NLRP12 在 Th17 细胞分化和实验性关节炎发展中的作用。我们发现，Nlrp12 小鼠发生严重关节炎，其特征是 Th17 介导的炎症反应加剧，关节痛觉过敏、膝关节肿胀和中性粒细胞浸润增加。将 Nlrp12 细胞过继转移到 WT 小鼠中重现了在 Nlrp12 小鼠中观察到的过度炎症反应，并且用抗 IL-17A 中和抗体治疗消除了 Nlrp12 小鼠的关节炎发展，表明 NLRP12 作为 Th17 细胞分化的抑制剂发挥作用。事实上，在 Th17 偏向培养条件下，Nlrp12 T 细胞中的 Th17 细胞分化明显增加。从机制上讲，我们发现 NLRP12 负调控 T 细胞中 IL-6 诱导的 STAT3 磷酸化。最后，STAT3 的药理学抑制减少了 Nlrp12 小鼠中观察到的 Th17 细胞分化和过度炎症性关节炎。因此，我们描述了 NLRP12 作为 Th17 细胞分化检查点抑制剂的新作用，该抑制剂控制实验性关节炎的严重程度。
