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

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 O'Reilly, Warren Alexander, Benjamin T. Kile, David L Vaux, James E Vince

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)982-990
Number of pages9
JournalEMBO Reports
Volume15
Issue number9
DOIs
Publication statusPublished - 1 Sep 2014
Externally publishedYes

Keywords

  • apoptosis
  • caspase-8
  • inflammasome
  • mitochondria
  • NLRP3

Cite this

Allam, Ramanjaneyulu ; Lawlor, Kate E ; Yu, Eric Chi-Wang ; Mildenhall, Alison L ; Moujalled, Donia M ; Lewis, Rowena S ; Ke, Francine ; Mason, Kylie D ; White, Michael J ; Stacey, Katryn J ; Strasser, Andreas ; O'Reilly, Lorraine ; Alexander, Warren ; Kile, Benjamin T. ; Vaux, David L ; Vince, James E. / Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. In: EMBO Reports. 2014 ; Vol. 15, No. 9. pp. 982-990.
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title = "Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming",
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.",
keywords = "apoptosis, caspase-8, inflammasome, mitochondria, NLRP3",
author = "Ramanjaneyulu Allam and Lawlor, {Kate E} and Yu, {Eric Chi-Wang} and Mildenhall, {Alison L} and Moujalled, {Donia M} and Lewis, {Rowena S} and Francine Ke and Mason, {Kylie D} and White, {Michael J} and Stacey, {Katryn J} and Andreas Strasser and Lorraine O'Reilly and Warren Alexander and Kile, {Benjamin T.} and Vaux, {David L} and Vince, {James E}",
year = "2014",
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doi = "10.15252/embr.201438463",
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Allam, R, Lawlor, KE, Yu, EC-W, Mildenhall, AL, Moujalled, DM, Lewis, RS, Ke, F, Mason, KD, White, MJ, Stacey, KJ, Strasser, A, O'Reilly, L, Alexander, W, Kile, BT, Vaux, DL & Vince, JE 2014, 'Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming' EMBO Reports, vol. 15, no. 9, pp. 982-990. https://doi.org/10.15252/embr.201438463

Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. / Allam, Ramanjaneyulu; Lawlor, Kate E; Yu, Eric Chi-Wang ; Mildenhall, Alison L; Moujalled, Donia M; Lewis, Rowena S; Ke, Francine; Mason, Kylie D; White, Michael J; Stacey, Katryn J; Strasser, Andreas; O'Reilly, Lorraine; Alexander, Warren; Kile, Benjamin T.; Vaux, David L; Vince, James E.

In: EMBO Reports, Vol. 15, No. 9, 01.09.2014, p. 982-990.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Allam, Ramanjaneyulu

AU - Lawlor, Kate E

AU - Yu, Eric Chi-Wang

AU - Mildenhall, Alison L

AU - Moujalled, Donia M

AU - Lewis, Rowena S

AU - Ke, Francine

AU - Mason, Kylie D

AU - White, Michael J

AU - Stacey, Katryn J

AU - Strasser, Andreas

AU - O'Reilly, Lorraine

AU - Alexander, Warren

AU - Kile, Benjamin T.

AU - Vaux, David L

AU - Vince, James E

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