2. Academic Validation
  3. A novel mechanism for macrophage pyroptosis in rheumatoid arthritis induced by Pol β deficiency

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

  • Cell Death Dis. 2022 Jul 6;13(7):583. doi: 10.1038/s41419-022-05047-6.
Lili Gu  # 1,  Yuling Sun  # 1,  Ting Wu  # 1,  Ge Chen 1,  Xiaojun Tang 2,  Lianfeng Zhao 1,  Lingfeng He 1,  Zhigang Hu 1,  Lingyun Sun 2,  Feiyan Pan 3,  Zhimin Yin 4,  Zhigang Guo 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China.
  • 2 Department of Rheumatology and Immunology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.
  • 3 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China. panfeiyan@njnu.edu.cn.
  • 4 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China. yinzhimin@njnu.edu.cn.
  • 5 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China. guo@njnu.edu.cn.
  • # Contributed equally.
PMID: 35794098 DOI: 10.1038/s41419-022-05047-6
Abstract

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.

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