Lyn prevents aberrant inflammatory responses to Pseudomonas infection in mammalian systems by repressing a SHIP-1-associated signaling cluster  

作　　者：Rongpeng Li Lizhu Fang Qinqin Pu Ping Lin Austin Hoggarth Huang Huang Xuefeng Li Guoping Li Min Wu 

机构地区：[1]Department of Biomedical Sciences,University of North Dakota,Grand Forks,North Dakota,USA [2]Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province,Jiangsu Normal University,Xuzhou,Jiangsu 221116,P.R.,China [3]State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University,and Collaborative Innovation Center for Biotherapy,Chengdu,China [4]Institute of Human Virology,Sun Yat-sen University,Guangzhou,China [5]Inflammation and Allergic Disease Research Unit,First Affiliated Hospital of Southwest Medical University,Luzhou,China

出　　处：《Signal Transduction and Targeted Therapy》2016年第1期10-20,共11页信号转导与靶向治疗（英文）

基　　金：This work was supported by National Institute of Health(AI109317-01A1 and AI109373-01).

摘　　要：The pleiotropic Src kinase Lyn has critical roles in host defense in alveolar macrophages against bacterial infection,but the underlying mechanism for Lyn-mediated inflammatory response remains largely elusive.Using mouse Pseudomonas aeruginosa infection models,we observed that Lyn^(−/−)mice manifest severe lung injury and enhanced inflammatory responses,compared with wild-type littermates.We demonstrate that Lyn exerts this immune function through interaction with IL-6 receptor and cytoskeletal protein Ezrin via its SH2 and SH3 domains.Depletion of Lyn results in excessive STAT3 activation,and enhanced the Src homology 2-containing inositol-5-phopsphatase 1(SHIP-1)expression.Deletion of SHIP-1 in Lyn^(−/−)mice(double knockout)promotes mouse survival and reduces inflammatory responses during P.aeruginosa infection,revealing the rescue of the deadly infectious phenotype in Lyn deficiency.Mechanistically,loss of SHIP-1 reduces NF-κB-dependent cytokine production and dampens MAP kinase activation through a TLR4-independent PI3K/Akt pathway.These findings reveal Lyn as a regulator for host immune response against P.aeruginosa infection through SHIP-1 and IL-6/STAT3 signaling pathway in alveolar macrophages.

关 键 词：SHIP INFLAMMATORY STAT3 

分 类 号：R73[医药卫生—肿瘤]