CellDeath&Differentiation(2019)26:99–114https://doi.org/10.1038/s41418-018-0212-6REVIEWARTICLEPyroptosisversusnecroptosis:similarities,differences,andcrosstalkDanielFrank1,2●JamesE.Vince1,2Received:9June2018/Revised:17August2018/Accepted:20September2018/Publishedonline:19October2018©ADMCAssociazioneDifferenziamentoeMorteCellulare2018Pyroptosisandnecroptosisrepresenttwopathwaysofgeneticallyencodednecroticcelldeath.Althoughthesecelldeathprogrammescanprotectthehostagainstmicrobialpathogens,theirdysregulationhasbeenimplicatedinavarietyofautoimmuneandauto-inflammatoryconditions.Thedisease-promotingpotentialofnecroptosisandpyroptosisislikelyaconsequenceoftheirabilitytoinducealyticcelldeath.Thiscellsuicidemechanism,distinctfromapoptosis,allowsthereleaseofimmunogeniccellularcontent,includingdamage-associatedmolecularpatterns(DAMPs),andinflammatorycytokinessuchasinterleukin-1β(IL-1β),totriggerinflammation.InthisReview,wediscussrecentdiscoveriesthathaveadvancedourunderstandingontheprimaryfunctionsofpyroptosisandnecroptosis,includingevidenceforthespecificcytokinesandDAMPsresponsiblefordrivinginflammation.Wecomparethesimilaranduniqueaspectsofpyroptotic-andnecroptotic-inducedmembranedamage,andexplorehowthesemayfunctionallyimpactdistinctintracellularorganellesandsignallingpathways.Wealsoexaminestudieshighlightingthecrosstalkthatcanoccurbetweennecroptosisandpyroptosissignalling,andevidencesupportingthephysiologicalsignificanceofthisconvergence.Ultimately,abetterunderstandingofthesimilarities,uniqueaspectsandcrosstalkofpyroptosisandnecroptosiswillinformastohowthesecelldeathpathwaysmightbemanipulatedfortherapeuticbenefit.Facts●Pyroptosisandnecroptosisarelytic,inflammatorytypesofprogrammedcelldeaththatrequirethemembranedamagingGSDMDandMLKLproteins,respectively.●Pyroptosisandnecroptosisprotectagainstinfectionsandcanbetriggeredbypathogenandhostmolecules.●AnumberofDAMPsarereleasedbypyroptoticandnecroptoticcelldeath,whichhavethecapacitytotriggerinflammatoryresponses.●GSDMDand...
