ReviewFieryCellDeath:PyroptosisintheCentralNervousSystemBrienneA.McKenzie,1,2VishvaM.Dixit,3andChristopherPower2,4,*Pyroptosis(‘fierydeath’)isaninflammatorytypeofregulatedcelldeath(RCD),whichoccursdownstreamofinflammasomeactivation.Pyroptosisismediateddirectlybytherecentlyidenti-fiedfamilyofpore-formingproteinsknownasgasdermins,thebestcharacterizedofwhichisgas-derminD(GSDMD).Recentinvestigationsimplicatepyroptosisinthepathogenesisofmultipleneurologicaldiseases.Inthisreview,wediscussmolecularmechanismsthatdrivepyroptosis,ev-idenceforpyroptosiswithintheCNS,andemergingtherapeuticstrategiesforitsinhibitioninthecontextofneurologicaldisease.Overview:CellDeathintheCNSRegulatedcelldeath(RCD)isanimportantfeatureofbraindevelopment,maintenanceofhomeo-stasis,andclearanceofinfectedortransformedcells.TwelvetypesofRCDexist[1],rangingfromnoninflammatory(e.g.,apoptosis)tohighlyproinflammatory(e.g.,pyroptosis,necroptosis),eachdefinedbyadistinctmolecularsignature.RCDisfundamentallydifferentfromnecrosis,whichisinstantaneous,catastrophic,andcannotbepreventedthroughpharmacologicalorgeneticinter-ventions[1].Apoptosis,whichisinitiatedbyperturbationsofthemicroenvironmentandprecipitatedbyexecu-tionercaspases,principallycaspase-3[1],hasbeenintensivelystudiedintheCNS[2].However,thereisagrowingappreciationfornonapoptoticinflammatorycelldeathasanimportantdetermi-nantofneurodegeneration.Inparticular,theproinflammatoryandlyticcelldeathprogramknownaspyroptosis(‘fierydeath’)hasemergedasapivotalfactorinneurologicaldisease,implicatedindisordersrangingfrommultiplesclerosis(MS)toAlzheimer’sdisease(AD)andtraumaticbraininjury(TBI).Multiplecelldeathmechanismscancontributeconcurrentlytothedevelopmentandprogressionofneurologicaldiseaseandmightdifferentiallyaffectspecificbrainregionsorcelltypeswithvaryinglevelsofsusceptibility.Understandingthecontributionofpyroptosisandothercelldeathpathwaystoneurologicaldiseaseisfundamentaltothedevelopmentofeffectivethera-peuticapproaches.Inthisreview,wediscussmolecu...
