Vagal-α7nAChR signaling is required for lung anti-inflammatory responses and arginase 1 expression during an influenza infection  

作　　者：Zhao-wei Gao Ling Li Yuan-yuan Huang Cai-qi Zhao Shuang-jia Xue Jie Chen Zhong-zhou Yang Jin-fu Xu Xiao Su 

机构地区：[1]Unit of Respiratory Infection and Immunity,Institut Pasteur of Shanghai,Chinese Academy of Sciences,Shanghai 200031,China [2]MOE Key Laboratory of Model Animal for Disease Study,Model Animal Research Center,Nanjing Biomedical Research Institute,Nanjing University,Nanjing 210061,China [3]Department of Pulmonary and Critical Care Medicine,Shanghai Pulmonary Hospital,Tongji University,Shanghai 200433,China

出　　处：《Acta Pharmacologica Sinica》2021年第10期1642-1652,共11页中国药理学报（英文版）

基　　金：This work is supported by NSFC programs 81730001,91942305,and 81970075;the Strategic Leading Project(B)of CAS XDPB0303;the International Collaboration project of CAS 153831KYSB20170043;Innovative Research Team of High-level Local Universities in Shanghai.

摘　　要：Vagal circuit-α7 nicotinic acetylcholine receptor(α7nAChR,coded by Chrna7)signaling can modulate lung proinflammatory responses.Arginase 1(ARG1)plays a crucial role in the resolution of lung inflammation.However,whether vagal-α7nAChR signaling can regulate lung inflammation and ARG1 expression during an influenza infection is elusive.Here,we found that lung and spleen IL-4^(+)cells and lung ARG1 expression were reduced;however,bronchoalveolar lavage(BAL)protein and leukocytes and lung inflammatory cytokines were increased in PR8(A/Puerto Rico/8/1934,H1N1)-infected vagotomized mice when compared to the control.In PR8-infectedα7nAChR-deficient mice,lung Arg1,Il10,and Socs3 expression and BAL Ly6C+CD206+cells were reduced.PR8-infected Chrna7^(+/+)recipient mice reconstituted with Chrna7^(−/−)bone marrow had a lower survival as compared to PR8-infected Chrna7^(+/+)recipient mice reconstituted with Chrna7^(+/+)bone marrow.Mechanistically,the activation ofα7nAChR by its agonist GTS-21 could enhance IL-4-induced Arg1 expression,reduced Nos2,and TNF-αexpression in PR8-infected bone marrow-derived macrophages(BMDM).Stimulation with IL-4 increased phosphorylation of STAT6 and activation ofα7nAChR increased STAT6 binding with the ARG1 promoter and relieved IL-4-induced H3K27me3 methylation by increasing JMJD3 expression in PR8-infected BMDM.Inhibition of JMJD3 increased H3K27me3 methylation and abolishedα7nAChR activation and IL-4 induced ARG1 expression.Activation ofα7nAChR also reduced phosphorylation of AKT1 and contained FOXO1 in the nucleus.Knockdown of Foxo1a reducedα7nAChR activation and IL-4 induced Arg1 expression in PR8-infected BMDM.Therefore,vagal-α7nAChR signaling is a novel therapeutic target for treating lung inflammatory responses during an influenza infection.

关 键 词：vagus circuits α7nAChR lung inflammation arginase 1 influenza A virus 

分 类 号：R56[医药卫生—呼吸系统] R96[医药卫生—内科学]