Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium

Immunity. 2015 Nov 17;43(5):987-97. doi: 10.1016/j.immuni.2015.10.010. Epub 2015 Nov 10.

Abstract

Defective neutrophils in patients with chronic granulomatous disease (CGD) cause susceptibility to extracellular and intracellular infections. Microbes must first be ejected from intracellular niches to expose them to neutrophil attack, so we hypothesized that inflammasomes detect certain CGD pathogens upstream of neutrophil killing. Here, we identified one such ubiquitous environmental bacterium, Chromobacterium violaceum, whose extreme virulence was fully counteracted by the NLRC4 inflammasome. Caspase-1 protected via two parallel pathways that eliminated intracellular replication niches. Pyroptosis was the primary bacterial clearance mechanism in the spleen, but both pyroptosis and interleukin-18 (IL-18)-driven natural killer (NK) cell responses were required for liver defense. NK cells cleared hepatocyte replication niches via perforin-dependent cytotoxicity, whereas interferon-γ was not required. These insights suggested a therapeutic approach: exogenous IL-18 restored perforin-dependent cytotoxicity during infection by the inflammasome-evasive bacterium Listeria monocytogenes. Therefore, inflammasomes can trigger complementary programmed cell death mechanisms, directing sterilizing immunity against intracellular bacterial pathogens.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / immunology
  • Bacterial Infections / immunology*
  • Calcium-Binding Proteins / immunology
  • Caspase 1 / immunology
  • Cell Death / immunology
  • Chromobacterium / immunology
  • Granulomatous Disease, Chronic / immunology
  • Inflammasomes / immunology*
  • Interferon-gamma / immunology
  • Interleukin-18 / immunology
  • Killer Cells, Natural / immunology*
  • Listeria monocytogenes / immunology
  • Listeriosis / immunology
  • Liver / immunology
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / immunology
  • Pyroptosis / immunology*
  • Spleen / immunology

Substances

  • Apoptosis Regulatory Proteins
  • Calcium-Binding Proteins
  • Inflammasomes
  • Interleukin-18
  • Ipaf protein, mouse
  • Interferon-gamma
  • Caspase 1