HMG‐CoA reductase inhibitors activate caspase‐1 in human monocytes depending on ATP release and P2X7 activation

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

关键词: statins;    IL‐;    1β;    mevalonate kinase deficiency;    isoprenoids;    inflammasome;   

DOI  :  10.1189/jlb.0812409

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

RecentstudieshavedemonstratedthestimulatoryeffectsofHMG‐CoAreductaseinhibitors,statins,onIL‐1βsecretioninmonocytesandsuggestacrucialroleforisoprenoidsintheinhibitionofcaspase‐1activity.Inthisstudy,wefurtherelucidatedthemolecularmechanismsunderlyingthestimulatoryeffectsofstatinsoncaspase‐1.ThreecommonlyrecognizedmechanisticmodelsforNLRP3inflammasomeactivation(i.e.,ATP/P2X7/K+efflux,ROSproduction,andlysosomalrupture)wereinvestigatedinstatin‐stimulatedhumanTHP‐1monocytes.WefoundthatfluvastatinandlovastatincansynergizewithLPStotriggerinflammasomeactivation.Moreover,statin‐inducedcaspase‐1activationandIL‐1βproductioninLPS‐primedTHP‐1cellsaredependentonGGPPdeficiencyandP2X7activation.Inparticular,increasedATPreleaseaccountsfortheactionofstatinsinP2X7activation.Wealsoprovideevidencethatstatin‐inducedmoderateROSelevationisinvolvedinthisevent.Moreover,thecathepsinBinhibitorwasshowntoreducestatin‐inducedIL‐1βsecretion.ConsistentlystatinscaninducecathepsinBactivationandlysosomalrupture,asevidencedbyLysoTrackerstaining.StatinsalsoincreaseintracellularATPsecretionandIL‐1βreleaseinprimaryhumanmonocytesandmurinemacrophages.Notably,exogenousATP‐elicitedP2X7activationandconsequentIL‐1βrelease,anindexofdirectNLRP3inflammasomeactivation,werenotalteredbystatins.Takentogether,statin‐inducedenhancementofinflammasomeactivationinmonocytesandmacrophagescoversmultiplemechanisms,includingincreasesinATPrelease,ROSproduction,andlysosomalrupture.Thesedatanotonlyshednewinsightintoisoprenylation‐dependentregulationofcaspase‐1butalsounmaskmechanismsforstatin‐elicitedinflammasomeactivation...

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