PI3Kγ controls leukocyte recruitment, tissue injury, and lethality in a model of graft‐versus‐host disease in mice

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: inflammation;    cell signaling;    cell migration;   

DOI  :  10.1189/jlb.0810464

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

PI3KγisthoughttomediateleukocytemigrationtoinjuredtissuesandmaybeimportantinthepathogenesisofvariousT‐lymphocyte‐dependentpathologies,includingautoimmuneandinflammatorydiseases.ThepresentstudyevaluatedtherelevanceofPI3KγindonorcellsforthepathogenesisofacuteGVHDusingamodelofadoptivetransferofsplenocytesfromWTorPI3Kγ−/−C57BL/6JmicetoB6D2F1mice,andmicethatreceivedPI3Kγ−/−cellsshowedreducedclinicalsignsofdisease,bacterialtranslocation,tissueinjury,andlethalityrates.Thiswasassociatedwithreducedproductionofproinflammatorycytokinesandchemokines(TNF‐α,IFN‐γ,CCL2,CCL3,andCCL5)andreducedinfiltrationofCD8+,CD4+,andCD11c+cellsinthesmallintestine.Mechanistically,inadditiontodecreasingproductionofproinflammatorymediators,absenceorpharmacologicalblockadeofPI3Kγwasassociatedwithdecreasedrollingandadhesionofleukocytestothemesentericmicrocirculation,asassessedbyintravitalmicroscopy.DespitedecreasedGVHD,therewasmaintainedGVLactivitywhenPI3Kγ−/−leukocytesweretransferredintoWTmice.Inconclusion,PI3KγplaysacriticalroleinGVHDbymediatingleukocyteinfluxandactivationintissues.PI3KγinhibitorsmaybeusefulinthetreatmentofGVHDinpatientsundergoingBMT...

【 授权许可】

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