The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity
Katharina S. Schneider,
Christina J. Groß,
Roland F. Dreier,
Benedikt S. Saller,
Ritu Mishra,
Oliver Gorka,
Rosalie Heilig,
Etienne Meunier,
Mathias S. Dick,
Tamara Ćiković,
Jan Sodenkamp,
Guillaume Médard,
Ronald Naumann,
Jürgen Ruland,
Bernhard Kuster,
Petr Broz,
Olaf Groß
Affiliations
Katharina S. Schneider
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
Christina J. Groß
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
Roland F. Dreier
Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland
Benedikt S. Saller
Institute of Neuropathology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Ritu Mishra
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
Oliver Gorka
Institute of Neuropathology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Rosalie Heilig
Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland
Etienne Meunier
Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland
Mathias S. Dick
Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland
Tamara Ćiković
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
Jan Sodenkamp
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
Guillaume Médard
Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany
Ronald Naumann
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
Jürgen Ruland
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
Bernhard Kuster
Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany
Petr Broz
Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland
Olaf Groß
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
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.