Department of pathology, Tianjin Hospital of Tianjin University, Tianjin, China.
Orthopedic Research Institute, Tianjin Hospital of Tianjin University, Tianjin, China.
Cell Mol Biol (Noisy-le-grand). 2023 Aug 31;69(8):179-184. doi: 10.14715/cmb/2023.69.8.27.
As a chronic inflammatory autoimmune disease, rheumatoid arthritis (RA) causes significant destruction to joints and cartilage. So far, from RA patients, the synovial cells and subsynovial tissues reflected the positive expression of IL-18, IL-1β, Caspase-1 and NLRP3, with the synovial tissues of those patients also expressing the zinc finger protein A20 at a significantly lower level compared with osteoarthritis (OA) ones. Thus, the inhibition of the NLRP3/caspase-1 signaling pathway can effectively down-regulate the expression of IL-1β, but when NLRP3 inflammasomes are activated, they can also shear GSDMD and induce pyroptosis. These suggest that the Gasdermin family of proteins, downstream of the NLRP3 inflammasome, could be involved in pyroptosis. Previous studies have shown that A20 contributes largely as an anti-inflammatory factor in many inflammatory diseases, but it remains unclear whether zinc finger protein A20, as an inhibitor of NLRP3 inflammasomes, can play a protective role against RA by inhibiting NLRP3 inflammasome-mediated pyroptosis. Therefore, this study aimed to verify the effects of zinc finger protein A20 on NLRP3/ Caspase-1-mediated pyroptosis in rheumatoid arthritis synovial fibroblasts (HFLS-RA) cells through cell experiments and clinical bidirectional verification, aim to understand the regulatory mechanism of A20 on RA. The results of clinical trials showed that NLRP3, Caspase-1, IL-1β and IL-18 were positively scattered in RA synovial cells and subsynovial tissue. The expression level of the zinc finger protein A20 in RA synovial tissues was significantly lower than that in OA synovial tissue and was negative, while zinc finger protein A20 was strongly positive in OA synovial tissue. In addition, HFLS-RA cells with siRNA-interfering zinc finger protein A20 were constructed at the cellular level, with the results also confirming that zinc finger protein A20 can play a protective role against RA by inhibiting NLRP3 inflammasome-mediated pyroptosis. In conclusion, this study is of great significance for understanding the role of the NLRP3-caspase-1-IL-1β/ pyroptosis signaling pathway in the occurrence and development of RA. It is expected that the results will provide a theoretical basis for the immune regulation of innate immunity in the occurrence and development of RA, while providing a new therapeutic target for the clinical treatment of RA.
作为一种慢性炎症性自身免疫性疾病，类风湿关节炎（RA）会导致关节和软骨的严重破坏。到目前为止，从 RA 患者中可以看出，滑膜细胞和滑膜下组织中 IL-18、IL-1β、Caspase-1 和 NLRP3 呈阳性表达，而与骨关节炎（OA）相比，这些患者的滑膜组织中锌指蛋白 A20 的表达水平明显降低。因此，抑制 NLRP3/caspase-1 信号通路可以有效下调 IL-1β 的表达，但当 NLRP3 炎性小体被激活时，它也可以剪切 GSDMD 并诱导细胞焦亡。这表明 NLRP3 炎性小体下游的 Gasdermin 蛋白家族可能参与了细胞焦亡。先前的研究表明，A20 在许多炎症性疾病中作为抗炎因子发挥着重要作用，但锌指蛋白 A20 是否作为 NLRP3 炎性小体的抑制剂，通过抑制 NLRP3 炎性小体介导的细胞焦亡来发挥对 RA 的保护作用仍不清楚。因此，本研究旨在通过细胞实验和临床双向验证来验证锌指蛋白 A20 对类风湿关节炎滑膜成纤维细胞（HFLS-RA）细胞中 NLRP3/Caspase-1 介导的细胞焦亡的影响，旨在了解 A20 对 RA 的调节机制。临床试验结果表明，NLRP3、Caspase-1、IL-1β 和 IL-18 在 RA 滑膜细胞和滑膜下组织中呈阳性散在分布。RA 滑膜组织中锌指蛋白 A20 的表达水平明显低于 OA 滑膜组织，呈阴性，而 OA 滑膜组织中锌指蛋白 A20 呈强阳性。此外，在细胞水平上构建了用 siRNA 干扰锌指蛋白 A20 的 HFLS-RA 细胞，结果也证实锌指蛋白 A20 通过抑制 NLRP3 炎性小体介导的细胞焦亡对 RA 发挥保护作用。总之，本研究对于了解 NLRP3-caspase-1-IL-1β/细胞焦亡信号通路在 RA 发生发展中的作用具有重要意义。预计该研究结果将为 RA 发生发展中固有免疫的免疫调节提供理论依据，同时为 RA 的临床治疗提供新的治疗靶点。
