AGTR1 inhibits pyroptosis and inflammatory cytokine secretion in rheumatoid arthritis fibroblast-like synoviocytes through the TGF-β pathway.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease. The hyperactivation of fibroblast-like synoviocytes (FLS) is a major contributor to synovial hyperplasia and cartilage destruction, and FLS pyroptosis plays a pivotal role in RA pathogenesis. This study aimed to investigate the mechanisms by which AGTR1 regulates FLS pyroptosis and inflammatory cytokine secretion in RA to identify potential therapeutic targets for RA. METHODS: Bioinformatic analysis assessed AGTR1 expression levels using the GSE21959 and GSE55235 datasets. qRT-PCR and western blot (WB) measured AGTR1 mRNA and protein levels in cell lines. Nigericin (a pyroptosis inducer), the TGF-β receptor I inhibitor SB505124, and the TGF-β neutralizing antibody 1D11 were administered to AGTR1-overexpressing RA-FLS, followed by western blot analysis of pyroptosis-related proteins. Flow cytometry, LDH assays, and propidium iodide staining evaluated pyroptosis levels. ELISA measured inflammatory cytokine secretion. WB confirmed TGF-β pathway activation. RESULTS: AGTR1 was downregulated in RA-FLS. AGTR1 overexpression suppressed ASC, NLRP3, cleaved caspase-1, and GSDMD-N expression, thereby alleviating pyroptosis in RA-FLS (P < 0.05). AGTR1 overexpression inhibited secretion of inflammatory cytokines and reduced lactate dehydrogenase release (P < 0.05). We demonstrated that AGTR1-mediated repression of pyroptosis and inflammatory cytokine secretion in RA-FLS was dependent on the TGF-β signaling pathway. CONCLUSION: AGTR1 inhibits pyroptosis and attenuates inflammatory cytokine secretion in RA-FLS through TGF-β. These findings suggest that AGTR1 induction or TGF-β pathway activation may ameliorate RA pathology.