The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity
| Autor: | Roland F. Dreier, Ritu Mishra, Jürgen Ruland, Katharina S. Schneider, Tamara Cikovic, Jan Sodenkamp, Oliver Gorka, Ronald Naumann, Rosalie Heilig, Mathias S. Dick, Petr Broz, Etienne Meunier, Benedikt S. Saller, Christina J. Groß, Bernhard Kuster, Olaf Groß, Guillaume Médard |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Programmed cell death Inflammasomes medicine.medical_treatment Interleukin-1beta Caspase 1 caspase-1 Animals Apoptosis Regulatory Proteins/metabolism Caspase 1/metabolism Caspase 8/metabolism Caspase Inhibitors/pharmacology Enzyme Activation/drug effects Francisella/physiology Immunity Innate Inflammasomes/metabolism Interleukin-1/metabolism Interleukin-1beta/metabolism Mice Inbred C57BL Pyroptosis/drug effects ASC IL-1 caspase-8 gasdermin inflammasome pyroptosis regulated necrosis Caspase 8 Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences medicine Secretion Francisella lcsh:QH301-705.5 Protease Chemistry Effector Intracellular Signaling Peptides and Proteins Pyroptosis Inflammasome Phosphate-Binding Proteins Caspase Inhibitors 3. Good health Cell biology ddc Enzyme Activation 030104 developmental biology lcsh:Biology (General) Apoptosis Regulatory Proteins Interleukin-1 medicine.drug |
| Zdroj: | Cell Reports, Vol 21, Iss 13, Pp 3846-3859 (2017) Cell Reports Cell reports, vol. 21, no. 13, pp. 3846-3859 |
| ISSN: | 2211-1247 |
| Popis: | Summary Inflammasomes activate the protease caspase-1, which cleaves interleukin-1β and interleukin-18 to generate the mature cytokines and controls their secretion and a form of inflammatory cell death called pyroptosis. By generating mice expressing enzymatically inactive caspase-1C284A, we provide genetic evidence that caspase-1 protease activity is required for canonical IL-1 secretion, pyroptosis, and inflammasome-mediated immunity. In caspase-1-deficient cells, caspase-8 can be activated at the inflammasome. Using mice either lacking the pyroptosis effector gasdermin D (GSDMD) or expressing caspase-1C284A, we found that GSDMD-dependent pyroptosis prevented caspase-8 activation at the inflammasome. In the absence of GSDMD-dependent pyroptosis, the inflammasome engaged a delayed, alternative form of lytic cell death that was accompanied by the release of large amounts of mature IL-1 and contributed to host protection. Features of this cell death modality distinguished it from apoptosis, suggesting it may represent a distinct form of pro-inflammatory regulated necrosis. Graphical Abstract Highlights • Interplay of caspase-1 and caspase-8 revealed by analysis of Caspase1C284A mice • GSDMD-dependent pyroptosis suppresses caspase-8 activation at the inflammasome • The inflammasome engages caspase-8-driven secondary pyroptosis and IL-1 release • GSDMD-independent mechanisms contribute to inflammasome-mediated host protection Schneider et al. show that, in the absence of GSDMD or caspase-1 protease activity (e.g., in Casp1C284A mice), the inflammasome engages an alternative type of lytic cell death and IL-1 release that contributes to immunity against infection. This secondary form of pyroptosis is dependent on apoptotic caspase activity but distinct from apoptosis. |
| Databáze: | OpenAIRE |
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