Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming

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dc.contributor.authorAllam, R.
dc.contributor.authorLawlor, K.E.
dc.contributor.authorYu, E.C.W.
dc.contributor.authorMildenhall, A.L.
dc.contributor.authorMoujalled, D.M.
dc.contributor.authorLewis, R.S.
dc.contributor.authorKe, F.
dc.contributor.authorMason, K.D.
dc.contributor.authorWhite, M.J.
dc.contributor.authorStacey, K.J.
dc.contributor.authorStrasser, A.
dc.contributor.authorO'Reilly, L.A.
dc.contributor.authorAlexander, W.
dc.contributor.authorKile, B.T.
dc.contributor.authorVaux, D.L.
dc.contributor.authorVince, J.E.
dc.date.issued2014
dc.description.abstractA current paradigm proposes that mitochondrial damage is a critical determinant of NLRP3 inflammasome activation. Here, we genetically assess whether mitochondrial signalling represents a unified mechanism to explain how NLRP3 is activated by divergent stimuli. Neither co-deletion of the essential executioners of mitochondrial apoptosis BAK and BAX, nor removal of the mitochondrial permeability transition pore component cyclophilin D, nor loss of the mitophagy regulator Parkin, nor deficiency in MAVS affects NLRP3 inflammasome function. In contrast, caspase-8, a caspase essential for death-receptor-mediated apoptosis, is required for efficient Toll-like-receptor-induced inflammasome priming and cytokine production. Collectively, these results demonstrate that mitochondrial apoptosis is not required for NLRP3 activation, and highlight an important non-apoptotic role for caspase-8 in regulating inflammasome activation and pro-inflammatory cytokine levels.
dc.description.statementofresponsibilityRamanjaneyulu Allam, Kate E Lawlor, Eric Chi-Wang Yu, Alison L Mildenhall, Donia M Moujalled, Rowena S Lewis, Francine Ke, Kylie D Mason, Michael J White, Katryn J Stacey, Andreas Strasser, Lorraine A O’Reilly, Warren Alexander, Benjamin T Kile, David L Vaux, James E Vince
dc.identifier.citationEMBO Reports, 2014; 15(9):982-990
dc.identifier.doi10.15252/embr.201438463
dc.identifier.issn1469-221X
dc.identifier.issn1469-3178
dc.identifier.orcidKile, B.T. [0000-0002-8836-8947]
dc.identifier.urihttp://hdl.handle.net/2440/123385
dc.language.isoen
dc.publisherEMBO Press
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1051210
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1009145
dc.relation.grant1014447
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1016701
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1016647
dc.rights© 2014 The Authors
dc.source.urihttps://doi.org/10.15252/embr.201438463
dc.subjectApoptosis; caspase-8; inflammasome; mitochondria; NLRP3
dc.titleMitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming
dc.typeJournal article
pubs.publication-statusPublished

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