Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming
Date
2014
Authors
Allam, R.
Lawlor, K.E.
Yu, E.C.W.
Mildenhall, A.L.
Moujalled, D.M.
Lewis, R.S.
Ke, F.
Mason, K.D.
White, M.J.
Stacey, K.J.
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Advisors
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Journal article
Citation
EMBO Reports, 2014; 15(9):982-990
Statement of Responsibility
Ramanjaneyulu 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
Conference Name
Abstract
A 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.
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© 2014 The Authors