The intersection of cell death and inflammasome activation

Cell Mol Life Sci. 2016 Jun;73(11-12):2349-67. doi: 10.1007/s00018-016-2205-2. Epub 2016 Apr 11.

Abstract

Inflammasomes sense cellular danger to activate the cysteine-aspartic protease caspase-1, which processes precursor interleukin-1β (IL-1β) and IL-18 into their mature bioactive fragments. In addition, activated caspase-1 or the related inflammatory caspase, caspase-11, can cleave gasdermin D to induce a lytic cell death, termed pyroptosis. The intertwining of IL-1β activation and cell death is further highlighted by research showing that the extrinsic apoptotic caspase, caspase-8, may, like caspase-1, directly process IL-1β, activate the NLRP3 inflammasome itself, or bind to inflammasome complexes to induce apoptotic cell death. Similarly, RIPK3- and MLKL-dependent necroptotic signaling can activate the NLRP3 inflammasome to drive IL-1β inflammatory responses in vivo. Here, we review the mechanisms by which cell death signaling activates inflammasomes to initiate IL-1β-driven inflammation, and highlight the clinical relevance of these findings to heritable autoinflammatory diseases. We also discuss whether the act of cell death can be separated from IL-1β secretion and evaluate studies suggesting that several cell death regulatory proteins can directly interact with, and modulate the function of, inflammasome and IL-1β containing protein complexes.

Keywords: Apoptosis; Caspase-1; Caspase-8; Inflammasome; MLKL; Necroptosis; Pyroptosis; RIPK3.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Caspase 1 / metabolism
  • Caspase 8 / metabolism
  • Humans
  • Inflammasomes / metabolism*
  • Inflammation / pathology
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Protein Kinases / metabolism
  • Pyroptosis / physiology*
  • Reactive Oxygen Species / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction / physiology*

Substances

  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Reactive Oxygen Species
  • MLKL protein, human
  • Protein Kinases
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Caspase 8
  • Caspase 1