2. Academic Validation
  3. ACPA-Induced ATP release and K+ efflux trigger NLRP3 inflammasome activation in rheumatoid arthritis

ACPA-Induced ATP release and K+ efflux trigger NLRP3 inflammasome activation in rheumatoid arthritis

  • Cell Commun Signal. 2025 Jul 1;23(1):302. doi: 10.1186/s12964-025-02331-8.
Li Cai # 1 2,  Kai Zhang # 3,  Jian Gao # 4,  Bing Xiao # 5,  Meng Li 6,  Xiangyun Meng 6,  Zhipeng Chen 5,  Xiaoling Chen 5,  Shixian Chen 7,  Juan Li 8 9
Affiliations

Affiliations

  • 1 Department of Nephrology and Rheumatology, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, China.
  • 2 Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
  • 3 Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
  • 4 Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 5 The First School of Clinical Medicine, Southern Medical University, Guangzhou, China.
  • 6 Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 7 Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou, China. shixian@smu.edu.cn.
  • 8 Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China. lijuan@smu.edu.cn.
  • 9 Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou, China. lijuan@smu.edu.cn.
  • # Contributed equally.
PMID: 40597276 DOI: 10.1186/s12964-025-02331-8
Abstract

Objectives: Anti-citrullinated protein antibodies (ACPA) is one of the key inducers of the initiation and maintenance of the immune-inflammatory response in Rheumatoid arthritis (RA), yet evidence is lacking on how ACPA drives the inflammatory response.

Methods: Citrullinated collagen-induced arthritis (C-CIA) were performed to evaluate the inflammatory response, especially NLRP3 inflammasome activation, in ACPA + arthritis model. Macrophages differentiated from THP-1 cell line were stimulated by ACPA purified from RA patients' serum, and the localization and interaction of molecules involved in NLRP3 inflammasome were analyzed by confocal microscopy and immunoprecipitation.

Results: Mice with arthritis induced by citrullinated Collagen showed higher levels of ACPA and enhanced activation of the NLRP3 inflammasome. This was evidenced by increased levels of IL-1β in the peripheral blood and more pronounced Pyroptosis and Caspase-1 (p20) expression in the synovial tissue, compared to mice induced with common Collagen. ACPA induced overactivation of NLRP3 inflammasome in THP-1-differentiated macrophages in vitro. ACPA recruits SFK kinase by binding to Integrin α5β1, induces C-terminal phosphorylation of Panx-1, and opens pannexin channel to release ATP; In addition, ACPA mediates the outflow of K+ into the extracellular by activating TWIK2 channel. These two signaling axes collectively lead to the activation of the NLRP3 inflammasome.

Conclusion: Our study demonstrates that ACPA can trigger both the priming and activation of the NLRP3 inflammasome. This process involves the release of ATP and the efflux of K+.

Keywords

ATP; Anti-citrullinated protein antibody; K+ efflux; Macrophages; NLRP3 inflammasome; Rheumatoid arthritis.

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