G protein‐coupled receptor kinase‐3‐deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses

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

关键词: chemokine receptor;    hematopoiesis;    granulocytes;    arthritis;   

DOI  :  10.1189/jlb.0213097

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Chemokinereceptorinteractionscoordinateleukocytemigrationininflammation.ChemokinereceptorsareGPCRsthatwhenactivated,arephosphorylatedbyGRKstoturnoffGprotein‐mediatedsignalingyetrecruitadditionalsignalingmachinery.Recently,GRK3wasidentifiedasanegativeregulatorofCXCL12/CXCR4signalingthatisdefectiveinhumanWHIMsyndrome.Here,wereportthatGRK3−/−miceexhibitnumerousfeaturesofhumanWHIM,suchasimpairedCXCL12‐mediateddesensitization,enhancedCXCR4signalingtoERKactivation,alteredgranulocytemigration,andamildmyelokathexis.Moreover,GRK3−/−protectsmicefromtwoacutemodelsofinflammatoryarthritis(K/BxNserumtransferandCAIA).Inthesegranulocyte‐dependentdiseasemodels,protectionofGRK3−/−miceismediatedbyretentionofcellsinthemarrow,fewercirculatinggranulocytesintheperipheralblood,andreducedgranulocytesinthejointsduringactiveinflammation.IncontrasttoWHIM,GRK3−/−micehaveminimalhypogammaglobulinemiaandaperipheralleukocytosiswithincreasedlymphocytesandabsentneutropenia.Thus,weconcludethatthelossofGRK3‐mediatedregulationofCXCL12/CXCR4signalingcontributestosome,butnotall,ofthecompleteWHIMphenotypeandthatGRK3inhibitionmaybebeneficialinthetreatmentofinflammatoryarthritis...

【 授权许可】

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