A novel mechanism for macrophage pyroptosis in rheumatoid arthritis induced by Pol β deficiency

Rheumatoid arthritis (RA) is a chronic and inflammatory autoimmune disease. Macrophage pyroptosis, a proinflammatory form of cell death, is critically important in RA; however, the detailed mechanism underlying pyroptosis induction is not yet well understood. Here, we report that DNA polymerase beta (Pol beta), a key enzyme in base excision repair, plays a pivotal role in RA pathogenesis. Our data shows that Pol beta expression is significantly decreased in peripheral blood mononuclear cells (PBMCs) from active RA patients and collagen-induced arthritis (CIA) mice, and Pol beta deficiency increases the incidence of RA, macrophage infiltration, and bone destruction in CIA mouse models. In vitro, experiments showed that Pol beta deficiency exacerbated macrophage pyroptosis induced by LPS plus ATP, while overexpression of Pol beta inhibited macrophage pyroptosis. Further characterization revealed that Pol beta knockout resulted in DNA damage accumulation and cytosolic dsDNA leakage, which activated the cGAS-STING-NF-kappa B signaling pathway and upregulated the expression of NLRP3, IL-1 beta, and IL-18. In conclusion, our findings clarify the influence of Pol beta on the development of RA and provide a detailed explanation for the STING-NF-kappa B pathway to induce macrophage pyroptosis.

Automated summary

This study reveals the crucial role of DNA polymerase beta in rheumatoid arthritis pathogenesis and provides a detailed explanation for the induction of macrophage pyroptosis through the STING-NF-kappa B pathway.