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

[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...

[学科分类] 生理学

[关键词] immunosuppression;chromatin remodeling;endotoxin tolerance