α7nAChR inhibits pyroptosis of rheumatoid arthritis synovial fibroblasts via the NLRP3/GSDMD pathway.

The pyroptosis of synovial fibroblasts (SFs) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA) and serves as a key driver of joint inflammation. Prior studies have elucidated the biological role of the α7 nicotinic acetylcholine receptor (α7nAChR) in RA; however, its influence on pyroptosis in RA-SFs remains to be fully understood. In this study, the human synovial fibroblast cell line MH7A was stimulated with TNF-α to mimic the characteristics of RA-SFs. The extent of pyroptosis was assessed by measuring the levels of lactate dehydrogenase (LDH) and pro-inflammatory cytokines in the cell supernatant, as well as Caspase-1 activation within the cells. The metastatic potential of the cells was evaluated by analyzing their migration, invasion capabilities, and matrix metalloproteinases (MMPs) secretion levels. Additionally, the activation status of the NLRP3 inflammasome was determined by detecting the expression levels of NLRP3/ GSDMD pathway-related proteins in the cells. The impact and molecular mechanisms of α7nAChR on pyroptosis in RA-SFs were investigated through the overexpression of α7nAChR and NLRP3. The results demonstrated that a high concentration of TNF-α induced RA-SFs to enhance GSDMD-N-mediated pyroptosis and inflammatory responses, while simultaneously reducing the expression of α7nAChR. Upon upregulation of α7nAChR, the pyroptosis of RA-SFs induced by TNF-α was attenuated. Additionally, the secretion of pro-inflammatory cytokines and MMPs was markedly reduced, the migration capacity of cells was suppressed, and the NLRP3/ GSDMD pathway was notably inhibited. Nevertheless, the aforementioned effects of α7nAChR upregulation on RA-SFs induced by TNF-α were partially counteracted by the overexpression of NLRP3. In summary, α7nAChR mitigates inflammation in TNF-α-induced RA-SFs by suppressing NLRP3/GSDMD pathway-mediated pyroptosis.