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ACPAs promote IL-1β 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-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.

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Acknowledgements

This work was supported by the National Basic Research Program “973 Grants” (2015CB553704), the National Basic Research Program of China grant (2014ZX09508002-002), and the National Key Research and Development Program of China grant (2017YFC0909000). We would also like to express our gratitude to Professor Zhinan Chen, who helped us design the experiments and provided us with essential experimental equipment.

Author contributions

X.D. and Z.Z. wrote the article. P.L. and X.F. assisted in carrying out the experiments and analyzing the data. F.L. helped to proofread the article. J.J. and P.Z. designed the experiments.

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Correspondence to Jianli Jiang or Ping Zhu.

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Dong, X., Zheng, Z., Lin, P. et al. ACPAs promote IL-1β production in rheumatoid arthritis by activating the NLRP3 inflammasome. Cell Mol Immunol 17, 261–271 (2020). https://doi.org/10.1038/s41423-019-0201-9

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