TheJournalofClinicalInvestigationREVIEW2022jci.orgVolume127Number6June2017IntroductionMultiplestudieshavesuggestedthatIL-1hasakeyroleinallograftrejection.Thegenerationofmature,highlybioactiveIL-1βrequiresproteolyticprocessingofitsprecursorsbytheenzymecaspase-1,alsoknownasIL-1β–convertingenzyme(ICE)(1,2).Caspase-1isactivatedthroughformationoftheinflammasomecomplex.Theterminflammasomewascoinedintheearly2000stodescribeahigh-molecular-weightcomplexpresentinthecytosolofcellsthatmediatedtheactivationofcaspases(3).Wenowknowthattherearemanyinflammasomesandthateachoneisinfluencedbyauniquepattern-recognitionreceptorresponsetoapathogen-associatedmolecularpattern(PAMP)oradamage-associatedmolecularpattern(DAMP).Thecanonicalinflammasomepathwayisresponsibleforacti-vatingcaspase-1inhumansandrodents.Forexample,engagementofNLR,NACHT,LRR,andPYDdomains-containingprotein3(NALP3;alsoknownascryopyrin),whichisencodedbyNLRP3inhumans,inducesoligomerizationandtherecruitmentofanadaptorproteinknownasapoptosis-associatedspeck-likeproteincontain-ingacaspaserecruitmentdomain(ASC).ASChastwodeath-folddomains,PYDandCARD,andactstobridgethesensormolecule,NLRP3,totheeffectormolecule,pro–caspase-1(Figure1).Aprox-imity-inducedprocessresultsintheformationofthemachinerycalledtheNLRP3inflammasome,whichcleavespro–caspase-1togeneratecaspase-1.Caspase-1drivestheprocessingofpro–IL-1βtoIL-1βaswellasthatofpro–IL-18toIL-18.Caspase-1alsoinducespyroptosis,aproinflammatoryprogrammedcelldeathviaaprocessthatincludescellswelling,membranerupture,andreleaseofintra-cellularinflammatorymediators(refs.4,5,andFigure1).Multiplereceptorproteinsareknowntoinduceassemblyofcanonicalinflammasomes.NLRP3actsasasensorformanyPAMPsandDAMPs.OtherexamplesincludeNLRP1,whichsens-esanthraxlethaltoxin;NLRC4,whichsensesflagella;andabsentinmelanoma2(AIM2)andpyrin,whichsensedouble-strandedDNA(4,5).Akintocaspase-1activationbythecanonicalinflam-masomemachinery,thereisanoncanonicalinflammasome,inwhichcytosolicLPSisdetecteddirectlybyinflam...
