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

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation.
• Macrophage pyroptosis, a pro-inflammatory cell death, is crucial in RA pathogenesis.
• The precise mechanisms driving pyroptosis in RA remain unclear.

Purpose of the Study:

• To investigate the role of DNA polymerase β (Pol β) in rheumatoid arthritis.
• To elucidate the molecular mechanisms linking Pol β to macrophage pyroptosis in RA.

Main Methods:

• Assessed Pol β expression in peripheral blood mononuclear cells (PBMCs) from RA patients and collagen-induced arthritis (CIA) mice.
• Utilized Pol β knockout and overexpression models in vitro and in vivo (CIA mice).
• Analyzed DNA damage, cytosolic dsDNA leakage, and the cGAS-STING-NF-κB signaling pathway.

Main Results:

• Pol β expression was significantly reduced in active RA patients and CIA mice.
• Pol β deficiency exacerbated RA incidence, macrophage infiltration, and bone destruction in CIA models.
• Pol β deficiency enhanced LPS/ATP-induced macrophage pyroptosis, leading to DNA damage, dsDNA leakage, and cGAS-STING-NF-κB pathway activation.

Conclusions:

• DNA polymerase β plays a critical role in regulating macrophage pyroptosis in rheumatoid arthritis.
• Pol β deficiency promotes RA development by activating the cGAS-STING-NF-κB pathway, increasing inflammatory cytokine production.
• Findings offer insights into RA pathogenesis and potential therapeutic targets related to Pol β and pyroptosis.