PROS1/AXL signaling protects mice from lethal influenza infection by inducing M2 macrophage polarizationOA
AXL,a member of the TAM(Tyro3,AXL,and Mertk)subfamily of RTKs,is abundantly expressed in lung tissue and has been implicated in viral infections and lung injury.PROS1,one of the ligands known to activate AXL,functions as an immunomodulator in many diseases.However,the role of PROS1/AXL signaling in influenza A virus(IAV)infection and infection‑induced lung injury is largely unknown.In this study,we find that the exogenous administration of PROS1 mitigates lung injury and protects mice from lethal infection by IAVs through the activation of AXL.PROS1 induces the phosphorylation of AXL,which in turn recruits Gab1 and p85,a regulatory subunit of PI3K,to form a complex that activates Gab1 and its downstream PI3K/AKT/mTOR in alveolar macrophages.Gab1 knockdown in vivo,or LY294002(a PI3K inhibitor),abolishes the PROS1/AXL‑induced protective activity against lethal influenza infection in mice.We also show that PROS1/AXL signaling induces M2 polarization of alveolar macrophages through Gab1 activation both in vitro and in vivo.Gab1 knockdown inhibits M2 macrophage accumulation in IAV‑infected lungs and attenuates the protective effect of PROS1.These results indicate that PROS1/AXL signaling can activate Gab1 in macrophages and induce macrophage polarization to an anti‑inflammatory M2 phenotype,thereby eliciting protective activity against lethal infection with IAVs.These data also highlight the PROS1/AXL signal as a novel therapeutic target for IAV infection.
Wenbo Zhu;Shao Wang;Shuangquan Liu;Qiang Fu;Hongbo Zhang
The First Affiliated Hospital,Clinical Medical Research Center,Hengyang Medical School,University of South China,Hengyang 421001,ChinaInstitute of Animal Husbandry and Veterinary Medicine,Fujian Academy of Agriculture Science,Fuzhou 350013,ChinaThe First Affiliated Hospital,Clinical Laboratory,Hengyang Medical School,University of South China,Hengyang 421001,ChinaThe First Affiliated Hospital,Department of Rheumatology and Immunology,Hengyang Medical School,University of South China,Hengyang 421001,ChinaDepartment of Pediatrics,University of Pittsburgh School of Medicine,Pittsburgh,PA 15224,USA
医药卫生
PROS1AXLmacrophagepolarizationinfluenza infection
《Acta Biochimica et Biophysica Sinica》 2026 (5)
P.1055-1068,14
supported by the grants from the Natural Science Foundation of Hunan Province(Nos.2024JJ5357 and 2023JJ40582 to W.Z.and Q.F)the Scientific Research Foundation of Hunan Provincial Education Department(Nos.24C0210 and 22C0214 to W.Z.and Q.F.).
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