ReviewEmergingActivatorsandRegulatorsofInflammasomesandPyroptosisYansongXue,1,2DanielEnosiTuipulotu,1,2WeiHongTan,1CallumKay,1andSiMingMan1,*Theinflammasomeisacytosolicimmunesignalingcomplexthatinducesinflammationandpyrop-tosis.Inflammasomecomplexesrespondtoavarietyofpathogens,aswellasdangerorhomeo-stasis-alteringsignals;theycanplaycriticalrolesinthedevelopmentofautoinflammatorycondi-tionsandcancer.Studieshavenowprovidedadditionalinsightsintotheactivationmechanismsandregulationofestablishedinflammasomecomplexes,includingNLRP1b,NLRP3,NOD-likere-ceptorfamilyapoptosisinhibitoryprotein(NAIP)–NLRC4,absentinmelanoma(AIM)2,caspase-11,andpyrin.NewactivatorsandregulatorsofemergingNLRP6andNLRP9binflammasomecomplexeshavealsobeendescribed.Wehighlightthelatestprogressinourunderstandingofthemolecularmechanismsgoverninginflammasomeactivationandpyroptosis,includingthedis-coveryofthepore-formingproteingasderminD(GSDMD).Wealsodiscusstheimportanceofinflammasomeactivatorsandregulatorsinhealthanddisease.AnOverviewofMammalianInflammasomeActivationTheinflammasome–acytosolicmultimericinnateimmunesignalingcomplex–hasemergedasacentralpillarofmammalianinnateimmunitysinceitsdiscoveryin2002[1].Formationofafunctionalinflammasomeisinitiatedbygermline-encodedpatternrecognitionreceptors(PRRs;seeGlos-sary),whicharecapableofsensingpathogen-associatedmolecularpatterns(PAMPs),danger-associatedmolecularpatterns(DAMPs),andhomeostasis-alteringmolecularprocesses(HAMPs)[2,3].Inflammasomeshavemostlybeenstudiedinthecontextofmacrophages,buthavebeendescribedinothermyeloidcells,notablydendriticcellsandneutrophils[4,5].Uponsensingaspe-cificPAMP,DAMP,orHAMP,certainPRRsrecruittheadaptorproteinapoptosis-associatedspeck-likeproteincontainingaCARD(ASC).ASCcontainstwodomains:apyrindomain(PYD,nottobeconfusedwiththeinflammasomesensorpyrin)andacaspaseactivationandrecruitmentdomain(CARD),which,throughhomotypicCARD–CARDinteractions,allowASCtocoupletheupstreamPRRtotheeffectorcysteineproteasecaspase-1[6](Figure1,KeyFig...
