SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy  

作　　者：Shuxin Liang Changlei Bao Zi Yang Shiyun Liu Yanan Sun Weitao Cao Ting Wang Tae-Hwi Schwantes-An John S.Choy Samisubbu Naidu Ang Luo Wenguang Yin Stephen M.Black Jian Wang Pixin Ran Ankit A.Desai Haiyang Tang 

机构地区：[1]State Key Laboratory of Respiratory Disease,National Clinical Research Center for Respiratory Disease,Guangdong Key Laboratory of Vascular Disease,Guangzhou Institute of Respiratory Health,The First Affiliated Hospital of Guangzhou Medical University,Guangzhou,Guangdong,China [2]College of Veterinary Medicine,Northwest A&F University,Yangling,Shaanxi,China [3]Department of Cellular Biology&Pharmacology,Herbert Wertheim College of Medicine,Miami,FL,USA [4]Department of Environmental Health Sciences,Robert Stempel College of Public Health and Social Work and Center for Translational Science,Florida International University,Port St.Lucie,FL,USA [5]Department of Medical and Molecular Genetics,Indiana University School of Medicine,Indianapolis,IN,USA [6]Department of Biology,The Catholic University of America,Washington,DC,USA [7]Krannert Institute of Cardiology,Department of Medicine,Indiana University,Indianapolis,IN,USA [8]Guangzhou Laboratory,Guangzhou,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第4期1901-1915,共15页信号转导与靶向治疗（英文）

基　　金：National Key Research and Development Program of China(2019YFE0119400);Natural Science Foundation of China(81770059,81970052 and 82000055);NIH NHLBI Grant(R01HL136603 to A.A.D.);National Science Foundation CCF PIPP Grant(2200138 to J.S.C.);ZHONGNANSHAN MEDICAL FOUNDATION OF GUANGDONG PROVINCE(ZNSA-2020013);Shenzhen Science and Technology Program(JCYJ20210324122410028);Open Project of State Key Laboratory of Respiratory Disease(SKLRD-OP-202301/202114).

摘　　要：Cardiopulmonary complications are major drivers of mortality caused by the SARS-CoV-2 virus.Interleukin-18,an inflammasomeinduced cytokine,has emerged as a novel mediator of cardiopulmonary pathologies but its regulation via SARS-CoV-2 signaling remains unknown.Based on a screening panel,IL-18 was identified amongst 19 cytokines to stratify mortality and hospitalization burden in patients hospitalized with COVID-19.Supporting clinical data,administration of SARS-CoV-2 Spike 1(S1)glycoprotein or receptor-binding domain(RBD)proteins into human angiotensin-converting enzyme 2(hACE2)transgenic mice induced cardiac fibrosis and dysfunction associated with higher NF-κB phosphorylation(pNF-κB)and cardiopulmonary-derived IL-18 and NLRP3 expression.IL-18 inhibition via IL-18BP resulted in decreased cardiac pNF-κB and improved cardiac fibrosis and dysfunction in S1-or RBD-exposed hACE2 mice.Through in vivo and in vitro work,both S1 and RBD proteins induced NLRP3 inflammasome and IL-18 expression by inhibiting mitophagy and increasing mitochondrial reactive oxygenation species.Enhancing mitophagy prevented Spike protein-mediated IL-18 expression.Moreover,IL-18 inhibition reduced Spike protein-mediated pNF-κB and EC permeability.Overall,the link between reduced mitophagy and inflammasome activation represents a novel mechanism during COVID-19 pathogenesis and suggests IL-18 and mitophagy as potential therapeutic targets.

关 键 词：NLRP3 expression CARDIOPULMONARY 

分 类 号：R563.1[医药卫生—呼吸系统]