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

Research output: Contribution to journalArticlepeer-review

209 Scopus citations

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-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. Schneider et al. show that, in the absence of GSDMD or caspase-1 protease activity (e.g., in Casp1 C284A 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.

Original languageEnglish
Pages (from-to)3846-3859
Number of pages14
JournalCell Reports
Volume21
Issue number13
DOIs
StatePublished - 26 Dec 2017

Keywords

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

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