TLR4, TLR7/8 agonist‐induced miR‐146a promotes macrophage tolerance to MyD88‐dependent TLR agonists

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

关键词: microRNA;    tolerance;   

DOI  :  10.1189/jlb.2A0515-197R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

TLRsfacilitatetherecognitionofpathogensbyimmunecellsandtheinitiationoftheimmuneresponse,leadingtotheproductionofproinflammatorycytokinesandchemokines.Productionofproinflammatorymediatorsbyinnateimmunecells,suchasmacrophages,istightlyregulatedtofacilitatepathogenclearancewhilelimitinganadverseimpactonhosttissue.ExposureofinnateimmunecellstoTLRligandsinducesastateoftemporaryrefractorinesstoasubsequentexposureofaTLRligand,aphenomenonreferredtoas“tolerance.”ThisstudysoughttoevaluatethemechanisticregulationofTLR4andTLR7/8ligand‐inducedtolerancetootherTLRsbymicroRNA‐146a.WiththeuseofTHP‐1macrophages,aswellashumanclassicandalternativemacrophages,wedemonstratethatprimingwithaTLR4agonist(LPS)oraTLR7/8agonist(R848)induceshomologousandheterologoustolerancetovariousTLRligandsinmacrophages,leadingtotheimpairedproductionofcytokinesandchemokines.WealsodemonstratethatoverexpressionofmicroRNA‐146aissufficienttomimicLPSorR848‐inducedhyporesponsiveness.Conversely,inhibitionofmicroRNA‐146aactivityleadstoLPS‐orR848‐inducedTLRhyper‐responsivenessinTLRsignalingtolerance.Furthermore,wedemonstratethatmicroRNA‐146adampenscytokineproductionfollowingaprimarystimuluswithMyD88‐dependentbutnotMyD88‐independentTLRpathways.Collectively,thesedataprovidecomprehensiveevidenceofthecentralroleofmicroRNA‐146ainTLRsignalingtolerancetoplasmamembrane,aswellasendosomalTLRligandsinhumanmacrophages...

【 授权许可】

CC BY