Non-canonical activation of inflammatory caspases by cytosolic LPS in innate immunity

Curr Opin Immunol. 2015 Feb;32:78-83. doi: 10.1016/j.coi.2015.01.007. Epub 2015 Jan 24.

Abstract

Lipopolysaccharide (LPS) is the major component of Gram-negative bacteria cell wall. In innate immunity, extracellular LPS is recognized by Toll-like receptor 4 to stimulate cytokine transcription. Recent studies suggest a 'non-canonical inflammasome' that senses cytoplasmic LPS and activates caspase-11 in mouse macrophages. Unexpectedly, biochemical studies reveal that caspase-11 and its human orthologs caspase-4/caspase-5 are LPS receptors themselves. Direct LPS binding induces caspase-4/caspase-5/caspase-11 oligomerization and activation, triggering cell pyroptosis and anti-bacterial defenses. Caspase-4/caspase-5/caspase-11 recognition of intracellular LPS requires bacterial escape from the vacuole; this process is promoted by interferon-inducible GTPases-mediated lysis of the bacteria-containing vacuole. Non-canonical activation of these inflammatory caspases by LPS not only represents a new paradigm in innate immunity but also critically determines LPS-induced septic shock in mice.

Publication types

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

MeSH terms

  • Animals
  • Caspases / metabolism*
  • Cytosol
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunity, Innate*
  • Inflammasomes / metabolism*
  • Inflammation / immunology*
  • Inflammation / metabolism*
  • Inflammation / microbiology
  • Lipopolysaccharides / immunology*
  • Lipopolysaccharides / metabolism
  • Mice
  • Protein Binding
  • Sepsis / immunology
  • Sepsis / metabolism
  • Sepsis / microbiology

Substances

  • Inflammasomes
  • Lipopolysaccharides
  • Caspases