2. Academic Validation
  3. ACPAs promote IL-1β production in rheumatoid arthritis by activating the NLRP3 inflammasome

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

  • Cell Mol Immunol. 2020 Mar;17(3):261-271. doi: 10.1038/s41423-019-0201-9.
Xiwen Dong  # 1 2 3,  Zhaohui Zheng  # 1 2,  Peng Lin  # 2 3,  Xianghui Fu 1 2,  Fanni Li 2 3,  Jianli Jiang 4 5,  Ping Zhu 6 7
Affiliations

Affiliations

  • 1 Department of Clinical Immunology, Branch of Immune Cell Biology, State Key Discipline of Cell Biology, PLA Specialized Research Institute of Rheumatology & Immunology, Xijing Hospital, Fourth Military Medical University, No. 127 West Changle Road, 710032, Xi'an, Shaanxi Province, China.
  • 2 National Translational Science Center for Molecular Medicine, 710032, Xi'an, China.
  • 3 Department of Cell Biology, State Key Discipline of Cell Biology, Fourth Military Medical University, 710032, Xi'an, China.
  • 4 National Translational Science Center for Molecular Medicine, 710032, Xi'an, China. jiangjl@fmmu.edu.cn.
  • 5 Department of Cell Biology, State Key Discipline of Cell Biology, Fourth Military Medical University, 710032, Xi'an, China. jiangjl@fmmu.edu.cn.
  • 6 Department of Clinical Immunology, Branch of Immune Cell Biology, State Key Discipline of Cell Biology, PLA Specialized Research Institute of Rheumatology & Immunology, Xijing Hospital, Fourth Military Medical University, No. 127 West Changle Road, 710032, Xi'an, Shaanxi Province, China. zhuping@fmmu.edu.cn.
  • 7 National Translational Science Center for Molecular Medicine, 710032, Xi'an, China. zhuping@fmmu.edu.cn.
  • # Contributed equally.
PMID: 30911117 DOI: 10.1038/s41423-019-0201-9
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.

Keywords

Anti-citrullinated protein antibodies; CD147; IL-1β; NLRP3 inflammasome; Rheumatoid arthritis.

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