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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism*
  • Caspase 1 / metabolism*
  • Caspase 8 / metabolism
  • Caspase Inhibitors / pharmacology
  • Enzyme Activation / drug effects
  • Francisella / physiology
  • Immunity, Innate
  • Inflammasomes / metabolism*
  • Interleukin-1 / metabolism*
  • Interleukin-1beta / metabolism
  • Mice, Inbred C57BL
  • Pyroptosis* / drug effects

Substances

  • Apoptosis Regulatory Proteins
  • Caspase Inhibitors
  • Gsdmd protein, mouse
  • Inflammasomes
  • Interleukin-1
  • Interleukin-1beta
  • Caspase 8
  • Caspase 1