ACPAs promote IL-1β production in rheumatoid arthritis by activating the NLRP3 inflammasome

Objectives: Anti-citrullinated protein antibodies (ACPAs) are a group of autoantibodies targeted against citrullinated proteins/peptides and are informative rheumatoid arthritis (RA) biomarkers. ACPAs also play a crucial role in RA pathogenesis, and their underlying mechanism merits investigation.

Methods: Immunohistochemical (IHC) assays were carried out to determine IL-1β levels in ACPA⁺ and ACPA^- RA patients. PBMC-derived monocytes were differentiated into macrophages before stimulation with ACPAs purified from RA patients. The localization and interaction of molecules were analyzed by confocal microscopy, co-IP, and surface plasmon resonance.

Results: In our study, we found that IL-1β levels were elevated in ACPA⁺ RA patients and that ACPAs promoted IL-1β production by PBMC-derived macrophages. ACPAs interacted with CD147 to enhance the interaction between CD147 and Integrin β1 and, in turn, activate the Akt/NF-κB signaling pathway. The nuclear localization of p65 promoted the expression of NLRP3 and pro-IL-1β, resulting in priming. Moreover, ACPA stimulation activated pannexin channels, leading to ATP release. The accumulated ATP bound to the P2X7 Receptor, leading to NLRP3 inflammasome activation.

Conclusions: Our study suggests a new hypothesis regarding IL-1β production in RA involving ACPAs, which may be a potential therapeutic target in RA treatment.