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The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity
Open accessAbstract
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-1 C284A , 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-1 C284A , 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.
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Citations
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Metadata
- Authors
- Schneider, K. S., Groß, C. J., Dreier, R. F., Saller, B. S., Mishra, R., Gorka, O., Heilig, R., Meunier, E., Dick, M. S., Ćiković, T., Sodenkamp, J., Médard, G., Naumann, R., Ruland, J., Kuster, B., Broz, P., & Groß, O.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 21
- Issue
- 13
- Pages
- 3846-3859
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2775971119
- Cited by
- 294
- References
- 43
- FWCI
- 8.93
- Type
- journal article
- Language
- en
- Open access
- gold
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