A novel role of the TNF-α/p65/IRF1 axis in aggravating rheumatoid arthritis through the induction of fibroblast-like synoviocytes pyroptosis

Engineering notes

Results IRF1 was significantly upregulated in RA tissues and TNF‐α‐treated FLSs.

Chinese explanation / 中文解读

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Original abstract

Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by aberrant proliferation and activation of fibroblast‐like synoviocytes (FLSs), leading to production of inflammatory mediators. Although interferon regulatory factor 1 (IRF1) is known to participate in immune regulation, its specific role and upstream activation mechanism in RA‐FLSs remain elusive. Methods IRF1 expression was assessed in RA synovial tissues, collagen‐induced arthritis (CIA) mouse synovium, and TNF‐α‐stimulated RA‐FLSs. Functional assays evaluated pyroptosis after IRF1 knockdown. Mechanistic investigations included ChIP‐seq, Cut‐and‐Run, and luciferase reporter assays to identify IRF1 target genes and promoter binding. In vivo , CIA mice were treated with IRF1 modulation to evaluate arthritis severity. Results IRF1 was significantly upregulated in RA tissues and TNF‐α‐treated FLSs. IRF1 suppression attenuated pyroptosis and reduced pyroptosis‐associated proteins (CASP1, GSDMD‐N, IL‐1β, IL‐18). TNF‐α activated p65, which directly bound to the IRF1 promoter, increasing IRF1 expression. IRF1 directly bound to the CASP1 promoter, enhancing CASP1 expression and pyroptosis. In CIA mice, IRF1 modulation markedly alleviated arthritis symptoms. Conclusion The TNF‐α–p65–IRF1–CASP1 axis drives pyroptosis in RA‐FLSs and contributes to RA pathogenesis, identifying IRF1 as a promising therapeutic target value.

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