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 m...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.展开更多
基金This work was supported by National Institute of Health(AI109317-01A1 and AI109373-01).
文摘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.
