Canonical Inflammasomes Drive IFN-γ to Prime Caspase-11 in Defense against a Cytosol-Invasive Bacterium

Cell Host Microbe. 2015 Sep 9;18(3):320-32. doi: 10.1016/j.chom.2015.07.016. Epub 2015 Aug 27.

Abstract

The inflammatory caspases 1 and 11 are activated in response to different agonists and act independently to induce pyroptosis. In the context of IL-1β/IL-18 secretion, however, in vitro studies indicate that caspase-11 acts upstream of NLRP3 and caspase-1. By contrast, studying infection in vivo by the cytosol-invasive bacterium Burkholderia thailandensis, we find that caspase-1 activity is required upstream of caspase-11 to control infection. Caspase-1-activated IL-18 induces IFN-γ to prime caspase-11 and rapidly clear B. thailandensis infection. In the absence of IL-18, bacterial burdens persist, eventually triggering other signals that induce IFN-γ. Whereas IFN-γ was essential, endogenous type I interferons were insufficient to prime caspase-11. Although mice transgenic for caspase-4, the human ortholog of caspase-11, cleared B. thailandensis in vivo, they did not strictly require IFN-γ priming. Thus, caspase-1 provides priming signals upstream of caspase-11 but not caspase-4 during murine defense against a cytosol-invasive bacterium.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Burkholderia / immunology*
  • Caspase 1 / metabolism*
  • Caspases / metabolism*
  • Caspases, Initiator / metabolism
  • Cytosol / microbiology*
  • Humans
  • Inflammasomes / metabolism*
  • Interferon-gamma / metabolism*
  • Interleukin-18 / metabolism*
  • Mice
  • Mice, Transgenic
  • Signal Transduction

Substances

  • Inflammasomes
  • Interleukin-18
  • Interferon-gamma
  • CASP4 protein, human
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator
  • Caspase 1