CCR1‐ and CCR5‐mediated inactivation of leukocytes by a nonglycosaminoglycan (non‐GAG)‐binding variant of n‐Nonanoyl‐CCL14 (NNY‐CCL14)

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

关键词: allergy;    chemokine;    leukocytes;    glycosaminoglycan;   

DOI  :  10.1189/jlb.0509366

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Interventiononchemokinereceptorstopreventdirectionalleukocytemigrationisapotentialtherapeuticstrategy.NNY‐CCL14isaCD26‐resistantleadmolecule,whichexertsitseffectsonmultiplechemokinereceptors(CCR1,CCR2,CCR3,andCCR5).TheinhibitoryeffectsofNNY‐CCL14inmurinemodelsofallergicairwayinflammationhavebeenassignedtoitsinteractionwithCCR1andCCR5.Inthisstudy,anon‐GAG‐bindingvariantofNNY‐CCL14wasgeneratedbymutatingbasicaminoacidswithintheidentifiedGAG‐binding49BBXB52motif.ThisCD26‐resistant,non‐GAGbindingvariant,NNY‐CCL14(G,A),doesnotpromoteCCR1‐dependentcellarrestonmodeledendothelium.ItsbiologicalactivitytestedonhumanandmurinechemokinereceptorsrevealeddistinguishingpropertiestoNNY‐CCL14.AssuggestedbyEC50valuesforintracellularcalciummobilization,NNY‐CCL14(G,A)demonstratedareducedabilitytoactivatehCCR1,butinternalizationanddesensitizationofhCCR1wereunperturbed.Surprisingly,itsactivityonhCCR3wasstronglyreduced,anditdidnotinternalizemCCR3.Asignificantlyreducedchemotacticactivityofeosinophilsandmonocyteswasobserved.AllbiologicaleffectsmediatedbyNNY‐CCL14(G,A)viahCCR5andmCCR5showednodifferencetoNNY‐CCL14.Inmicetreatedi.v.withNNY‐CCL14(G,A),asustainedinvivodown‐modulationofCCR5wasachievedover3h.Therefore,NNY‐CCL14(G,A)inactivatesleukocytesbydesensitizingandinternalizingmultiplechemokinereceptors,thusrenderingthemunresponsivetofurtherstimulationbynaturalligands.Whenadministeredsystemically,NNY‐CCL14(G,A)maymodulateleukocytefunctionspriortotheirinteractionwithotherendothelium‐boundchemokinesexpressedunderpathophysiologicalconditions,suchasallergicinflammation...

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