Xiwen Dong1,2,3, Zhaohui Zheng1,2, Peng Lin2,3, Xianghui Fu1,2, Fanni Li2,3, Jianli Jiang4,5, Ping Zhu6,7. 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.
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.
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.
Entities:
Keywords:
Anti-citrullinated protein antibodies; CD147; IL-1β; NLRP3 inflammasome; Rheumatoid arthritis
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