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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 publication

DOI

10.15252/embr.201438463

Type

Journal article

Publication Date

09/2014

Volume

15

Pages

982 - 990

Keywords

NLRP3, apoptosis, caspase‐8, inflammasome, mitochondria, Apoptosis, Autophagy, Bone Marrow Cells, Carrier Proteins, Caspase 8, Cells, Cultured, Cyclophilins, Humans, Inflammasomes, Interleukin-1beta, Mitochondria, Mitochondrial Degradation, NLR Family, Pyrin Domain-Containing 3 Protein, Toll-Like Receptors, Ubiquitin-Protein Ligases