Prolyl‐4‐hydroxylase domain 3 (PHD3) is a critical terminator for cell survival of macrophages under stress conditions

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

关键词: hypoxia;    oxygen sensing;    angiopoietin‐;    like protein;    HIF;   

DOI  :  10.1189/jlb.2HI1013-533R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Onamolecularlevel,cellssensechangesinoxygenavailabilitythroughthePHDs,whichregulatetheproteinstabilityoftheα‐subunitofthetranscriptionfactorHIF.Especially,PHD3hasbeenadditionallyassociatedwithapoptoticcelldeath.WehypothesizedthatPHD3playsaroleincell‐fatedecisionsinmacrophages.Therefore,myeloid‐specificPHD3−/−micewerecreatedandanalyzed.PHD3−/−BMDMshowednoalteredHIF‐1αorHIF‐2αstabilizationorincreasedHIFtargetgeneexpressioninnormoxiaorhypoxia.MacrophageM1andM2polarizationwasunchangedlikewise.ComparedwithmacrophagesfromWTlittermates,PHD3−/−BMDMexhibitedasignificantreductioninTUNEL‐positivecellsafterserumwithdrawalortreatmentwithstauroandSNAP.Underthesameconditions,PHD3−/−BMDMalsoshowedlessAnnexinVstaining,whichisrepresentativeformembranedisruption,andindicatedareducedearlyapoptosis.Inanunbiasedtranscriptomescreen,wefoundthatAngptl2expressionwasreducedinPHD3−/−BMDMunderstressconditions.AdditionofrAngptl2rescuedtheantiapoptoticphenotype,demonstratingthatitisinvolvedinthePHD3‐mediatedresponsetowardapoptoticstimuliinmacrophages...

【 授权许可】

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