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Cell Rep. 2017 Dec 26;21(13):3846-3859. doi: 10.1016/j.celrep.2017.12.018.

The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity.

Author information

1
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany.
2
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany.
3
Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
4
Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
5
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, 81675 Munich, Germany.
6
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, 81675 Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany.
7
Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany.
8
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
9
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, 81675 Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany; German Center for Infection Research (DZIF), partner site Munich, 81675 Munich, Germany.
10
Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany; Center for Integrated Protein Science Munich (CIPSM), 81377 Munich, Germany.
11
Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland; Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
12
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany; Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, 81675 Munich, Germany. Electronic address: olaf.gross@uniklinik-freiburg.de.

Abstract

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.

KEYWORDS:

ASC; IL-1; caspase-1; caspase-8; gasdermin; inflammasome; pyroptosis; regulated necrosis

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