期刊
EMBO REPORTS
卷 15, 期 9, 页码 982-990出版社
WILEY-BLACKWELL
DOI: 10.15252/embr.201438463
关键词
apoptosis; caspase-8; inflammasome; mitochondria; NLRP3
资金
- Independent Research Institutes Infrastructure Support Scheme, Australian National Health and Medical Research Council [361646]
- SCOR, Leukemia and Lymphoma Society of America [7001-13]
- Sylvia and Charles Viertel Foundation
- Leukemia Foundation of Australia
- Cancer Council of Victoria
- Australian Cancer Research Fund
- Victorian State Government Operational Infrastructure Support Grant
- Foundation Louis-Jeantet
- Swiss National Science Foundation
- Institute for Arthritis Research
- [1051210]
- [1009145]
- [1014447]
- [1016701]
- [1016647]
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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