Elevated postinjury thrombospondin 1–CD47 triggering aids differentiation of patients' defective inflammatory CD1a+dendritic cells

[摘要] AsubsetofPtsdevelopsdysfunctionalMOtoinflammatoryDCdifferentiationandimmunosuppression.MDDC,anewlydescribedDCsubset,ispivotalininitiatingantibacterialresponses.EndogenousproteinsareknowntoalterMOtoMDDCdifferentiation.Inparticular,trauma‐elevatedTSP‐1,aproteinthatisknowntoaffectMOfunctions,couldtriggerMDDCdifferentiationdefects.WehypothesizedthatTSP‐1‐derangeddifferentiationofinflammatoryCD1a+MDDCwouldnegativelyalteractivationofimmunefunctions,therebyincreasingtheriskofpostinjuryinfections.Post‐traumaincreasedTSP‐1levelsinpatients'plasmaandMOcorrelatedwithtwodistinctMDDCdifferentiationdysfunctions:thepreviouslydescribeddecreasedCD1a+DCyieldsbutalso,developmentofanimmunoincompetentCD1a+MDDC.ThePts'developmentofDysfDCcorrelatedtoincreasedinfectiouscomplications.TSP‐1triggereditsinhibitoryreceptor,CD47,activatinganinhibitoryphosphatase,SHP‐1.IncreasedpSHP‐1,decreasedantigenprocessing,anddepressedTcellstimulationcharacterizedPtDysfDC.TSP‐1mimicsaddedduringCntMDDCdifferentiationdepressedCD1a+DCyieldsbutmoreimportantly,alsoinduceddefectiveCD1a+MDDC,reproducingPts'MDDCdifferentiationdysfunctions.CD47triggeringduringCntMDDCdifferentiationincreasedSHP‐1activation,inhibitingIL‐4‐inducedSTAT‐6activation(criticalforCD1a+MDDCdifferentiation).SHP‐1inhibitionduringMDDCdifferentiationinthepresenceofTSP‐1mimicsrestoredpSTAT‐6levelsandCD1a+MDDCimmunogenicity.Thus,postinjury‐elevatedTSP‐1candecreaseCD1a+DCyieldsbutmorecritically,alsoinducesSHP‐1hyperactivity,deviatingMDDCdifferentiationtodefectiveCD1a+inflammatoryMDDCsbyinhibitingSTAT‐6...

[学科分类] 生理学

[关键词] monocyte‐derived DC;SHP‐1 phosphatase;trauma patient