Rac1‐dependent secretion of platelet‐derived CCL5 regulates neutrophil recruitment via activation of alveolar macrophages in septic lung injury

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

关键词: chemokines;    sepsis;    CLP;    inflammation;   

DOI  :  10.1189/jlb.4A1214-603R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Accumulatingevidencesuggestthatplateletsplayanimportantroleinregulatingneutrophilrecruitmentinsepticlunginjury.Herein,wehypothesizedthatplatelet‐derivedCCL5mightfacilitatesepsis‐inducedneutrophilaccumulationinthelung.AbdominalsepsiswasinducedbyCLPinC57BL/6mice.CLPincreasedplasmalevelsofCCL5.PlateletdepletionandtreatmentwiththeRac1inhibitorNSC23766markedlyreducedCCL5intheplasmaofsepticmice.Moreover,Rac1inhibitioncompletelyinhibitedproteasePAR4‐inducedsecretionofCCL5inisolatedplatelets.ImmunoneutralizationofCCL5decreasedCLP‐inducedneutrophilinfiltration,edemaformation,andtissueinjuryinthelung.However,inhibitionofCCL5functionhadnoeffectonCLP‐inducedexpressionofMac‐1onneutrophils.TheblockingofCCL5decreasedplasmaandlunglevelsofCXCL1andCXCL2insepticanimals.CCL5hadnoeffectonneutrophilchemotaxisinvitro,suggestinganindirecteffectofCCL5onneutrophilrecruitment.IntratrachealchallengewithCCL5increasedaccumulationofneutrophilsandformationofCXCL2inthelung.AdministrationoftheCXCR2antagonistSB225002abolishedCCL5‐inducedpulmonaryrecruitmentofneutrophils.IsolatedalveolarmacrophagesexpressedsignificantlevelsoftheCCL5receptorsCCR1andCCR5.Inaddition,CCL5triggeredsignificantsecretionofCXCL2fromisolatedalveolarmacrophages.Notably,intratrachealadministrationofclodronatenotonlydepletedmiceofalveolarmacrophagesbutalsoabolishedCCL5‐inducedformationofCXCL2inthelung.Takentogether,ourfindingssuggestthatRac1regulatesplateletsecretionofCCL5andthatCCL5isapotentinducerofneutrophilrecruitmentinsepticlunginjuryviaformationofCXCL2inalveolarmacrophages...

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