Rapid externalization of 27‐kDa heat shock protein (HSP27) and atypical cell death in neutrophils treated with the sphingolipid analog drug FTY720

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

关键词: phosphatidylserine;    apoptosis;    necroptosis;    MLKL;    NADPH oxidase;   

DOI  :  10.1189/jlb.3VMA1114-522RR

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Thesphingolipidanalogfingolimodisknowntoinduceapoptosisoftumorcellsandlymphocytes.Itseffectonneutrophilshasnotbeeninvestigatedsofar.Here,wedescribeafingolimod‐inducedatypicalcelldeathmechanisminhumanneutrophils,characterizedbyrapidtranslocationofheatshockprotein27tothecellsurface,extensivecellswellingandvacuolization,atypicalchromatinstainingandnuclearmorphology,andphosphorylationofmixedlineagekinasedomain‐likeprotein.Fingolimodalsoinducestypicalapoptoticfeatures,includingrapidexternalizationofphosphatidylserineandactivationofcaspase‐8.Fingolimod‐inducedneutrophildeathisindependentofsphingosine‐1‐phosphatereceptorsandpositivelyregulatedbyproteinphosphataseA.Externalizationofphosphatidylserineandheatshockprotein27canbepartiallyinhibitedbyinhibitorsofcaspase‐8[Z‐Ile‐Glu(O‐Me)‐Thr‐Asp(O‐Me)‐fluoromethylketone],receptor‐interactingproteinkinase1(necrostatin‐1),receptor‐interactingproteinkinase3(necrosulfonamide),andheatshockprotein90[geldanamycinand17‐(dimethylaminoethylamino)‐17‐demethoxygeldanamycin].Furthermore,NADPHoxidase1inhibitionwithdiphenyleneiodoniumchlorideprotectsneutrophilsagainstfingolimod‐mediatedcelldeath.Overall,theseobservationssuggestthatfingolimodactsthroughamechanisminvolvingthenecrosomesignalingcomplexandtheoxidativestressmachinery...

【 授权许可】

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