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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. 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. 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. 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+.
Li et al. (Tue,) studied this question.