ReviewOrchestrationofNLRP3InflammasomeActivationbyIonFluxesTaoGong,1,2YanqingYang,3TengchuanJin,1WeiJiang,1,5,*andRongbinZhou1,4,5,*TheassemblyoftheNLRP3inflammasomecanpromotethereleaseofIL-1b/IL-18andinitiatepyroptosis.Accordingly,thedysregulationofNLRP3inflamma-someactivationisinvolvedinavarietyofhumandiseases,includinggout,diabetes,andAlzheimer’sdisease.NLRP3cansenseavarietyofstructurallyunrelatedpathogen-associatedmolecularpatterns(PAMPs)ordanger-asso-ciatedmolecularpatterns(DAMPs)totriggerinflammation,buttheunifyingmechanismofNLRP3activationisstillpoorlyunderstood.Increasingevidencesuggeststhatintracellularions,suchasK+,Ca2+,andCl�,haveasignificantroleinNLRP3inflammasomeactivation.Here,wereviewthecurrentknowledgeabouttheroleofionicfluxesinNLRP3inflammasomeactivationanddiscusshowdisturbancesinintracellularioniclevelsorchestratedifferentsignalingeventsupstreamofNLRP3.MultipleSignalingPathwaysConvergeonNLRP3InflammasomeActivationTheNLRP3inflammasome(seeGlossary)isanintracellularproteincomplexcomprisingthesensormoleculeNLRP3,theadaptorproteinapoptosis-associatedspeck-likeproteincontainingaCARD(ASC),andpro-caspase-1.Onceactivated,NLRP3interactswithASCviaahomotypicpyrindomainandinducestheaggregationofASCintoalargeproteinspeck[1].Subsequently,aggregatedASCrecruitspro-caspase-1viaitscaspaseactivationandrecruit-ment(CARD)domain,whichpromotesitsself-cleavageandactivation[2].Activecaspase-1thencleavesthecytokineprecursorspro-IL-1bandpro-IL-18toproducematureIL-1bandIL-18andpromoteinflammatoryimmuneresponses[3].Inaddition,caspase-1alsocleavesgasderminD(GSDMD)toreleaseitsN-terminaldomain.Thisdomaincanformporesatthemembraneand,thus,inducesarapid,proinflammatoryformofcelldeathtermed‘pyroptosis’,whichactsasadefensemechanismagainstintracellularpathogeninfections[4].AlthoughNLRP3inflammasomeactivationisinvolvedintheclearanceofmicrobialinfections,theaberrantactivationoftheNLRP3inflammasomeisalsoinvolvedintheinitiationandprogressofvariousautoinflammatoryorchronicinflammatory...
