The C‐terminal acidic tail is responsible for the inhibitory effects of HMGB1 on efferocytosis

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

关键词: inflammation;    neutrophils;    macrophages;    phagocytosis;    apoptosis;   

DOI  :  10.1189/jlb.0510262

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

HMGB1wasdescribedoriginallyasanuclearproteininvolvedinDNAbindingandtranscriptionalregulation.However,HMGB1alsohasanextracellularroleasapotentmediatorofinflammationandcandiminishtheuptakeofapoptoticcellsbyphagocytes,aprocesscalledefferocytosis.ToexplorethemechanismresponsiblefortheabilityofHMGB1toinhibitefferocytosis,weexaminedtheroleoftheC‐terminalacidictail,aregionofHMGB1thathasbeenshowntoparticipateinspecificintramolecularinteractions.DeletionoftheC‐terminaltailabrogatedtheabilityofHMGB1todecreasemurinemacrophageingestionofapoptoticneutrophilsandtodiminishphagocytosis‐inducedactivationofErkandRac‐1inmacrophages.WefoundthatRAGEplaysamajorroleinefferocytosis,anddeletionoftheC‐terminaltailofHMGB1preventedbindingofHMGB1toRAGEbutnottoothermacrophagereceptorsinvolvedinefferocytosis,suchastheαVβ3integrin.WhereasHMGB1decreasedingestionofapoptoticneutrophilssignificantlybyalveolarmacrophagesunderinvivoconditionsinthelungsofmice,thiseffectwaslostwhentheC‐terminalacidictailwasabsentfromHMGB1.TheseresultsdemonstratethattheHMGB1C‐terminaltailisresponsiblefortheinhibitoryeffectsofHMGB1onphagocytosisofapoptoticneutrophilsunderinvitroandinvivoconditions...

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