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

• Published in: Cell death & disease 2022-07, Vol.13 (7), p.583-583, Article 583
• Main Authors: Gu, Lili, Sun, Yuling, Wu, Ting, Chen, Ge, Tang, Xiaojun, Zhao, Lianfeng, He, Lingfeng, Hu, Zhigang, Sun, Lingyun, Pan, Feiyan, Yin, Zhimin, Guo, Zhigang
• Format: Article
• Language: English
• Subjects: 13/109; 13/51; 13/89; 14/19; 14/28; 38/77; 631/250/1932; 631/337/1427/1429; 64/60; 82/80; 96/21; Animal models; Animals; Antibodies; Arthritis, Experimental - genetics; Arthritis, Rheumatoid - genetics; Autoimmune diseases; Base excision repair; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell death; Collagen; Deoxyribonucleic acid; DNA; DNA damage; DNA-directed DNA polymerase; IL-1β; Immunology; Interleukin 1; Interleukin 18; Leukocytes, Mononuclear; Life Sciences; Lipopolysaccharides; Macrophages; Mice; NF-kappa B; NF-κB protein; Nucleotidyltransferases; Peripheral blood mononuclear cells; Pyroptosis; Rheumatoid arthritis; Signal transduction
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-05047-6

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 β (Pol β), a key enzyme in base excision repair, plays a pivotal role in RA pathogenesis. Our data shows that Pol β expression is significantly decreased in peripheral blood mononuclear cells (PBMCs) from active RA patients and collagen-induced arthritis (CIA) mice, and Pol β deficiency increases the incidence of RA, macrophage infiltration, and bone destruction in CIA mouse models. In vitro, experiments showed that Pol β deficiency exacerbated macrophage pyroptosis induced by LPS plus ATP, while overexpression of Pol β inhibited macrophage pyroptosis. Further characterization revealed that Pol β knockout resulted in DNA damage accumulation and cytosolic dsDNA leakage, which activated the cGAS-STING-NF-κB signaling pathway and upregulated the expression of NLRP3, IL-1 β, and IL-18. In conclusion, our findings clarify the influence of Pol β on the development of RA and provide a detailed explanation for the STING-NF-κB pathway to induce macrophage pyroptosis.