DNA of neutrophil extracellular traps promote NF-κBdependent autoimmunity via cGAS/TLR9 in chronic obstructive pulmonary disease  

作　　者：Jun Chen Tao Wang Xiaoou Li Lijuan Gao Ke Wang Mengxin Cheng Zijian Zeng Lei Chen Yongchun Shen Fuqiang Wen 

机构地区：[1]Department of Respiratory and Critical Care Medicine,West China Hospital,West China School of Medicine,and Division of Pulmonary Diseases,State Key Laboratory of Biotherapy,Sichuan University,Chengdu,Sichuan 610041,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第7期3040-3055,共16页信号转导与靶向治疗（英文）

基　　金：supported by the 1•3•5 project for disciplines of excellence,West China Hospital,Sichuan University[grant numbers ZYGD23009];the National Natural Science Foundation of China(NSFC)[grant numbers 81830001,81670038,81800015 and 31871157];the Natural Science Foundation of Sichuan Province[Grant number 2022NSFSC0603];the China Postdoctoral Science Foundation[Grant numbers 2019T120851 and 2018M643501];the Fundamental Research Funds for the Central Universities(the Postdoctoral Foundation of Sichuan University)[Grant number 2018SCU12028].

摘　　要：Chronic obstructive pulmonary disease(COPD)is characterised by persistent airway inflammation even after cigarette smoking cessation.Neutrophil extracellular traps(NETs)have been implicated in COPD severity and acute airway inflammation induced by short-term cigarette smoke(CS).However,whether and how NETs contribute to sustained airway inflammation in COPD remain unclear.This study aimed to elucidate the immunoregulatory mechanism of NETs in COPD,employing human neutrophils,airway epithelial cells(AECs),dendritic cells(DCs),and a long-term CS-induced COPD mouse model,alongside cyclic guanosine monophosphate-adenosine monophosphate synthase and toll-like receptor 9 knockout mice(cGAS-^(−/−)TLR9^(−/−));Additionally,bronchoalveolar lavage fluid(BALF)of COPD patients was examined.Neutrophils from COPD patients released greater cigarette smoke extract(CSE)-induced NETs(CSE-NETs)due to mitochondrial respiratory chain dysfunction.These CSE-NETs,containing oxidatively-damaged DNA(NETs-DNA),promoted AECs proliferation,nuclear factor kappa B(NF-κB)activation,NF-κB-dependent cytokines and type-I interferons production,and DC maturation,which were ameliorated/reversed by silencing/inhibition of cGAS/TLR9.In the COPD mouse model,blocking NETs-DNA-sensing via cGAS^(−/−)and TLR9^(−/−)mice,inhibiting NETosis using mitoTEMPO,and degrading NETs-DNA with DNase-I,respectively,reduced NETs infiltrations,airway inflammation,NF-κB activation and NF-κBdependent cytokines,but not type-I interferons due to IFN-α/βreceptor degradation.Elevated NETs components(myeloperoxidase and neutrophil elastase activity)in BALF of COPD smokers correlated with disease severity and NF-κB-dependent cytokine levels,but not type-I interferon levels.In conclusion,NETs-DNA promotes NF-κB-dependent autoimmunity via cGAS/TLR9 in long-term CS exposure-induced COPD.Therefore,targeting NETs-DNA and cGAS/TLR9 emerges as a potential strategy to alleviate persistent airway inflammation in COPD.

关 键 词：INFLAMMATION TLR9 NEUTROPHIL 

分 类 号：R563[医药卫生—呼吸系统]