Macrophage migration arrest due to a winning balance of Rac2/Sp1 repression over β‐catenin‐induced PLD expression

[摘要] Monocytesandneutrophilsinfiltrateintotissuesduringinflammationandstayforextendedperiodsoftimeuntiltheinitialinsultisresolvedorsometimesremainevenlongerinthecaseofchronicinflammation.Themechanismastowhyphagocytesbecomeimmobilizedaftertheinitialcellmigrationeventisnotunderstoodcompletely.Here,weshowthatoverexpressionorhyperactivationofRac2decreasessustainedchemotacticresponsesofmacrophagestoMCP‐1/CCL2.TheresultingleukocytearrestisnotcausedbyadiminishedavailabilityofthecytokinereceptorCCR2thatremainsintactduringMCP‐1stimulation.WeshowanovelmechanismthatlinkstheRac2‐dependentarrestofchemotaxistodecreasedexpressionofPLD2throughthetranscriptionregulatorSp1.ProlongedRac2activityleadstonuclearoveractivationofSp1,whichactsasarepressorforPLD2.Also,anothersignalingcomponentplaysaregulatoryrole:β‐catenin.Althoughearlytimesofstimulation(∼20min)withMCP‐1/CCL2resultedinactivationofβ‐cateninwithapositiveeffectonPLD2,after∼3hofstimulation,thelevelsofβ‐cateninwerereducedandnotabletopreventthenegativeeffectofRac2onPLD2activity.Thisisanovelmolecularmechanismunderlyingimmobilizationofmonocyte/macrophagemigrationthatisimportantforthephysiologicalmaintenanceofleukocytesatthesiteofinflammation.Ifthisimmobilizationisprolongedenough,itcouldleadtochronicinflammation...

[学科分类] 生理学

[关键词] granulocyte;monocyte signaling cascade;chemotaxis;gene expression regulation;cell migration