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

Cell Reports

Guillaume Médard¹  Bernhard Kuster¹  Roland F. Dreier²  Petr Broz²  Etienne Meunier²  Rosalie Heilig²  Mathias S. Dick²  Jürgen Ruland³  Christina J. Groß³  Katharina S. Schneider³  Ritu Mishra³  Olaf Groß³  Tamara Ćiković³  Jan Sodenkamp³  Benedikt S. Saller⁴  Oliver Gorka⁴  Ronald Naumann⁵ 

[1] Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany;Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland;Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany;Institute of Neuropathology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany;Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany;

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

DOI  :  10.1016/j.celrep.2017.12.018

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown