Lipid rafts couple class A scavenger receptors to phospholipase A2 activation during macrophage adhesion

摘要

SR‐AmediatedmacrophageadhesiontomodifiedECMproteinsinaprocessthatinvolvesphysicalattachmentofSR‐AtomodifiedECMandactivationofLyn‐PI3KandPLA2‐12/15‐lipoxygenasesignalingpathways.Structurally,SR‐A‐mediatedcelladhesionrequiresa6‐aamembrane‐proximalcytoplasmicmotif.However,themechanismthatcouplesSR‐A‐mediatedadhesiontoactivationofthesedistinctsignalingpathwaysisnotknown.Forotheradhesionreceptors,includingintegrins,localizationincholesterol‐richLRsisanimportantmechanismforcouplingthereceptorwiththeactivationofspecificsignalingpathways.WehypothesizedthatSR‐A‐mediatedmacrophageadhesionmightalsoinvolveLRs.OurresultsdemonstratethatSR‐AisenrichedinLRsinHEKcellsthatheterologouslyexpressSR‐Aandinmacrophagesthatendogenouslyexpressedthereceptor.WefurthershowthatatruncatedSR‐Aconstruct(SR‐AΔ1–49),whichmediatescelladhesionbutnotligandinternalization,isalsoenrichedinLRs,suggestinganassociationbetweenLRsandSR‐A‐dependentcelladhesion.Toexaminethisassociationmoredirectly,weusedthecholesterolchelatorMβCDtodepletecholesterolanddisruptLRfunction.WefoundthatcholesteroldepletionsignificantlydecreasedSR‐A‐mediatedmacrophageadhesion.WefurthershowthatdecreasedSR‐A‐dependentmacrophageadhesionfollowingcholesteroldepletionresultsfromtheinhibitionofPLA2butnotPI3Kactivation.Overall,ourresultsdemonstrateanimportantroleforLRsinselectivelycouplingSR‐AwithPLA2activationduringmacrophageadhesion...