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

ABSTRACT:

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-1? 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-1? levels were elevated in ACPA⁺ RA patients and that ACPAs promoted IL-1? production by PBMC-derived macrophages. ACPAs interacted with CD147 to enhance the interaction between CD147 and integrin ?1 and, in turn, activate the Akt/NF-?B signaling pathway. The nuclear localization of p65 promoted the expression of NLRP3 and pro-IL-1?, 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-1? production in RA involving ACPAs, which may be a potential therapeutic target in RA treatment.

SUBMITTER: Dong X 

PROVIDER: S-EPMC7052171 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature