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 ro...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-1βlevels in ACPA+and ACPA−RA patients.PBMCderived 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-1βlevels were elevated in ACPA+RA patients and that ACPAs promoted IL-1βproduction by PBMC-derived macrophages.ACPAs interacted with CD147 to enhance the interaction between CD147 and integrinβ1 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-1βproduction in RA involving ACPAs,which may be a potential therapeutic target in RA treatment.展开更多
基金This work was supported by the National Basic Research Program“973 Grants”(2015CB553704)the National Basic Research Program of China grant(2014ZX09508002-002)+1 种基金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.
文摘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-1βlevels in ACPA+and ACPA−RA patients.PBMCderived 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-1βlevels were elevated in ACPA+RA patients and that ACPAs promoted IL-1βproduction by PBMC-derived macrophages.ACPAs interacted with CD147 to enhance the interaction between CD147 and integrinβ1 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-1βproduction in RA involving ACPAs,which may be a potential therapeutic target in RA treatment.
