Cholinergic dysfunction-induced insufficient activation of alpha7 nicotinic acetylcholine receptor drives the development of rheumatoid arthritis through promoting protein citrullination via the SP3/PAD4 pathway

查看全文 作　　者：Changjun [1]Lv;Minghui [2]Sun;Yilei [1]Guo;Wenxin [1]Xia;Simiao [1]Qiao;Yu [1]Tao;Yulai [1]Fang;Qin [1]Zhang;Yanrong [1]Zhu;Yusufu [2]Yalikun;Yufeng [1]Xia;Zhifeng [1]Wei;Yue [1]Dai 机构地区：[1]Department of Pharmacology of Chinese Materia Medica,School of Traditional Chinese Pharmacy,China Pharmaceutical University,Nanjing 211198,China;[2]Division of Sports Medicine and Adult Reconstructive Surgery,Department of Orthopedic Surgery,Nanjing Drum Tower Hospital,the Affiliated Hospital of Nanjing University Medical School,Nanjing 210008,China 出　　处：《Acta Pharmaceutica Sinica B》索引2023年第13卷第4期,共16页 基　　金：supported by the“Double First-Class”University Project(CPU2022QZ31,China)。 摘　　要：Both cholinergic dysfunction and protein citrullination are the hallmarks of rheumatoid arthritis(RA),but the relationship between the two phenomena remains unclear.We explored whether and how cholinergic dysfunction accelerates protein citrullination and consequently drives the development of RA.Cholinergic function and protein citrullination levels in patients with RA and collageninduced arthritis(CIA)mice were collected.In both neuron-macrophage coculture system and CIA mice,the effect of cholinergic dysfunction on protein citrullination and expression of peptidylarginine deiminases(PADs)was assessed by immunofluorescence.The key transcription factors for PAD4 expression were predicted and validated.Cholinergic dysfunction in the patients with RA and CIA mice negatively correlated with the degree of protein citrullination in synovial tissues.The cholinergic or alpha7 nicotinic acetylcholine receptor(a7nAChR)deactivation and activation resulted in the promotion and reduction of protein citrullination in vitro and in vivo,respectively.Especially,the activation deficiency of a7nAChR induced the earlier onset and aggravation of CIA.Furthermore,deactivation of a7nAChR increased the expression of PAD4 and specificity protein-3(SP3)in vitro and in vivo.Our results suggest that cholinergic dysfunction-induced deficient a7nAChR activation,which induces the expression of SP3 and its downstream molecule PAD4,accelerating protein citrullination and the development of RA. 关 键 词：Rheumatoid arthritis CITRULLINATION Cholinergic dysfunction a7nAChR Peptidylarginine deiminase 4 Specificity protein-3 Collagen-induced arthritis Neuron-macrophage coculture system