Cigarette smoke inhibits efferocytosis via deregulation of sphingosine kinase signaling: reversal with exogenous S1P and the S1P analogue FTY720

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

关键词: macrophage;    phagocytosis;    COPD;    SPHK subcellular localization;   

DOI  :  10.1189/jlb.3A1015-471R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Alveolarmacrophagesfromchronicobstructivepulmonarydiseasepatientsandcigarettesmokersaredeficientintheirabilitytophagocytoseapoptoticbronchialepithelialcells(efferocytosis).Wehypothesizedthatthedefectismediatedviainhibitionofsphingosinekinasesand/ortheirsubcellularmislocalizationinresponsetocigarettesmokeandcanbenormalizedwithexogenoussphingosine‐1‐phosphateorFTY720(fingolimod),amodulatorofsphingosine‐1‐phosphatesignaling,whichhasbeenshowntobeclinicallyusefulinmultiplesclerosis.Measurementofsphingosinekinase1/2activitiesby[32P]‐labeledsphingosine‐1‐phosphaterevealeda30%reductionofsphingosinekinase1(P<0.05)andanonsignificantdecreaseofsphingosinekinase2inTHP‐1macrophagesafter1hcigarettesmokeextractexposure.Byconfocalanalysismacrophagesphingosinekinase1proteinwasnormallylocalizedtotheplasmamembraneandcytoplasmandsphingosinekinase2tothenucleusandcytoplasmbutabsentatthecellsurface.Cigarettesmokeextractexposure(24h)ledtoaretractionofsphingosinekinase1fromtheplasmamembraneandsphingosinekinase1/2clumpingintheGolgidomain.Selectiveinhibitionofsphingosinekinase2with25µMABC294640ledto36%inhibitionofefferocytosis(P<0.05);10µMsphingosinekinaseinhibitor/5C(sphingosinekinase1‐selectiveinhibitor)inducedanonsignificantinhibitionofefferocytosis,butitscombinationwithABC294640ledto56%inhibition(P<0.01vs.controland<0.05vs.singleinhibitors).Cigarettesmoke‐inhibitedefferocytosiswassignificantly(P<0.05)reversedtonear‐controllevelsinthepresenceof10–100nMexogenoussphingosine‐1‐phosphateorFTY720,andFTY720reducedcigarettesmoke‐inducedclumpingofsphingosinekinase1/2intheGolgidomain.Thesedatastronglysupportaroleofsphingosinekinase1/2inefferocytosisandasnoveltherapeutictargetsinchronicobstructivepulmonarydisease...

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