Epigenetically modulated LRRC33 acts as a negative physiological regulator for multiple Toll‐like receptors

[摘要] ThemembersofaLRRfamilyplaycrucialrolesintheactivationofinnateandadaptiveimmuneresponses.WereportedpreviouslythatLRRC33,atransmembraneproteinoftheLRRfamily,mightpotentiallyaffectTLR‐mediatedactivity.Here,wedemonstratethatLRRC33isanegativephysiologicalregulatorformultipleTLRs.Lrrc33−/−andLrrc33+/−miceweremoresusceptibletoTLRligandchallenges.ThemacrophagesandDCsfromLrrc33−/−miceproducedmoreproinflammatorycytokinesthanthoseofWTmicethroughincreasedactivationofMAPKandNF‐κB.SilencingLRRC33alsopromotedmultipleTLR‐mediatedactivationinhumanmoDCs.Notably,LRRC33expressioncouldbedown‐regulatedbyTLRligandsLPS,polyI:C,orPGNthroughH3K4me3andH3K27me3modification.InLPS‐conditionedmoDCs,reducedenrichmentofH3K4me3andincreasedH3K27me3couldbeobservedatthepromoterregionofLRRC33.Furthermore,silencingH3K4me3‐associatedfactorsMLLandRBBP5notonlydecreasedtheenrichmentofH3K4me3butalsodown‐regulatedexpressionofLRRC33,whereastheexpressionofLRRC33wasup‐regulatedaftersilencingH3K27me3‐associatedfactorsEZH2andEED.Thus,ourresultssuggestthatLRRC33andTLRsmayformanegative‐feedbackloop,whichisimportantforthemaintenanceofimmunehomeostasis...

[学科分类] 生理学

[关键词] dendritic cell;macrophage;H3K4me3;H3K27me3