REVIEWSUMMARY◥CELLDEATHPATHWAYSProgrammednecrosisininflammation:TowardidentificationoftheeffectormoleculesDavidWallach,*Tae-BongKang,ChristopherP.Dillon,DouglasR.Green*BACKGROUND:Inflammatorylesionsoftencontaindeadcells.Celldeathindevelop-mentalprocessescharacteristicallyoccursbyapoptosis,aformofprogrammedcelldeathinwhichdyingcellsarephagocytizedbeforeundergoingmembranedamage.Ininflam-mation,however,celldeathisoftennecrotic,wherecellularconstituentsarereleasedaftermembranerupture.Thedeathofcellsinin-flammationwasuntilrecentlythoughttoresultfromotherchangesintheinflamedtissue.Thisviewhaschanged,however,owingtoseveralfindings:thatnecroticcelldeathcanbeinducedbybiomoleculesknowntoini-tiateinflammation[suchasthecytokinetumornecrosisfactor(TNF)orthepathogencom-ponentlipopolysaccharide(LPS)];thatitcanbedictatedinaprogrammedmannerbydis-tinctsetsofsignalingmechanisms;andthatityieldsreleaseofsomecellularcomponentscapableoffacilitatinginflammation.Itnowseemsprobablethatnecroticcelldeathisnotalwaysaconsequenceofinflammation,butissometimesratheritstrigger.Toconfirmthisnotion,weneedreliabletoolsfordetectionofprogrammednecrosisinvivo.Becausepro-grammednecrosiscannotbedistinguishedmorphologicallyfromaccidentalcelldeath,itsidentificationininflamedtissuesmustbebasedonitsdistinctivemoleculardetails.ADVANCES:Wenowhavequitedetailedknowledgeofthemechanismsinitiatingapoptoticcelldeathandthoseinitiatingtwoformsofprogrammednecrosis—necroptosisandpyroptosis.Apoptosisistriggeredbypro-teasesofthecaspasefamily.Necroptosisistriggeredbyspecificproteinkinases,mostcru-ciallyreceptor-interactingproteinkinase–3(RIPK3).Pyroptosisistriggeredbycaspasesdistinctfromthosemediatingapoptosis,andwhoseactivationyieldsproteolyticactivationoftheinflammatorycytokinesinterleukin-1b(IL-1b)andIL-18.Allofthesemolecularini-tiatorsofdeathprograms,however,alsocon-tributetotheinitiationofnondeadlycellfunctionsandarethusnotspecificmarkersfordeath.Twoproteinswererecentlyfoundtoactfurtherdownstreaminthesignalingpathw...
