SIRT1 inhibition during the hypoinflammatory phenotype of sepsis enhances immunity and improves outcome

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

关键词: immunosuppression;    chromatin remodeling;    endotoxin tolerance;   

DOI  :  10.1189/jlb.3MA0114-034RR

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Mechanism‐basedsepsistreatmentsareunavailable,andtheirincidenceisrisingworldwide.Deathsoccurduringtheearlyacutephaseofhyperinflammationorsubsequentpostacutehypoinflammatoryphasewithsustainedorganfailure.Theacutesepsisphaseshiftsrapidly,andmultipleattemptstotreatearlyexcessiveinflammationhaveuniformlyfailed.WereportedinasepsiscellmodelandhumansepsisbloodleukocytesthatnuclearNAD+sensorSIRT1deacetylaseremodelschromatinatspecificgenesetstoswitchtheacute‐phaseproinflammatoryresponsetohypoinflammatory.Importantly,SIRT1chromatinreprogrammingisreversible,suggestingthatinhibitionofSIRT1mightreversepostacute‐phasehypoinflammation.Wetestedthisconceptinsepticmice,usingthehighlyspecificSIRT1inhibitorEX‐527,asmallmoleculethatclosestheNAD+bindingsiteofSIRT1.Strikingly,whenadministered24haftersepsis,alltreatedanimalssurvived,whereasonly40%ofuntreatedmicesurvived.EX‐527treatmentreversedtheinabilityofleukocytestoadhereatthesmallintestineMVI,reversedinvivoendotoxintolerance,increasedleukocyteaccumulationinperitoneum,andimprovedperitonealbacterialclearance.Mechanistically,theSIRT1inhibitorrestoredrepressedendothelialE‐selectinandICAM‐1expressionandPSGL‐1expressionontheneutrophils.SystemicbenefitsofEX‐527treatmentincludedstabilizedbloodpressure,improvedmicrovascularbloodflow,andashifttowardproimmunemacrophagesinspleenandbonemarrow.OurfindingsrevealthatmodifyingtheSIRT1NAD+axismayprovideanovelwaytotreatsepsisinitshypoinflammatoryphase...

【 授权许可】

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