NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for Colitis

Cell. 2011 May 27;145(5):745-57. doi: 10.1016/j.cell.2011.04.022. Epub 2011 May 12.

Abstract

Inflammasomes are multiprotein complexes that function as sensors of endogenous or exogenous damage-associated molecular patterns. Here, we show that deficiency of NLRP6 in mouse colonic epithelial cells results in reduced IL-18 levels and altered fecal microbiota characterized by expanded representation of the bacterial phyla Bacteroidetes (Prevotellaceae) and TM7. NLRP6 inflammasome-deficient mice were characterized by spontaneous intestinal hyperplasia, inflammatory cell recruitment, and exacerbation of chemical colitis induced by exposure to dextran sodium sulfate (DSS). Cross-fostering and cohousing experiments revealed that the colitogenic activity of this microbiota is transferable to neonatal or adult wild-type mice, leading to exacerbation of DSS colitis via induction of the cytokine, CCL5. Antibiotic treatment and electron microscopy studies further supported the role of Prevotellaceae as a key representative of this microbiota-associated phenotype. Altogether, perturbations in this inflammasome pathway, including NLRP6, ASC, caspase-1, and IL-18, may constitute a predisposing or initiating event in some cases of human IBD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteria / classification
  • Bacteroidetes
  • Chemokine CCL5 / metabolism
  • Colitis / chemically induced
  • Colitis / immunology*
  • Colitis / microbiology*
  • Colitis / physiopathology
  • Colon / immunology
  • Colon / microbiology*
  • Dextran Sulfate
  • Disease Susceptibility
  • Inflammasomes / immunology*
  • Interleukin-18 / immunology
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*

Substances

  • Ccl5 protein, mouse
  • Chemokine CCL5
  • Inflammasomes
  • Interleukin-18
  • Nod-like receptor pyrin domain-containing protein 6, mouse
  • Receptors, Cell Surface
  • Dextran Sulfate