Absence of intestinal PPARγ aggravates acute infectious colitis in mice through a lipocalin-2-dependent pathway

PLoS Pathog. 2014 Jan;10(1):e1003887. doi: 10.1371/journal.ppat.1003887. Epub 2014 Jan 23.

Abstract

To be able to colonize its host, invading Salmonella enterica serovar Typhimurium must disrupt and severely affect host-microbiome homeostasis. Here we report that S. Typhimurium induces acute infectious colitis by inhibiting peroxisome proliferator-activated receptor gamma (PPARγ) expression in intestinal epithelial cells. Interestingly, this PPARγ down-regulation by S. Typhimurium is independent of TLR-4 signaling but triggers a marked elevation of host innate immune response genes, including that encoding the antimicrobial peptide lipocalin-2 (Lcn2). Accumulation of Lcn2 stabilizes the metalloproteinase MMP-9 via extracellular binding, which further aggravates the colitis. Remarkably, when exposed to S. Typhimurium, Lcn2-null mice exhibited a drastic reduction of the colitis and remained protected even at later stages of infection. Our data suggest a mechanism in which S. Typhimurium hijacks the control of host immune response genes such as those encoding PPARγ and Lcn2 to acquire residence in a host, which by evolution has established a symbiotic relation with its microbiome community to prevent pathogen invasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Acute-Phase Proteins / genetics
  • Acute-Phase Proteins / immunology*
  • Animals
  • Cell Line
  • Colitis / genetics
  • Colitis / immunology*
  • Colitis / microbiology
  • Colitis / pathology
  • Humans
  • Immune Evasion*
  • Lipocalin-2
  • Lipocalins / genetics
  • Lipocalins / immunology*
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / immunology
  • Mice
  • Mice, Knockout
  • Oncogene Proteins / genetics
  • Oncogene Proteins / immunology*
  • PPAR gamma / genetics
  • PPAR gamma / immunology*
  • Salmonella Infections / genetics
  • Salmonella Infections / immunology*
  • Salmonella Infections / pathology
  • Salmonella typhimurium / immunology*
  • Salmonella typhimurium / pathogenicity
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology

Substances

  • Acute-Phase Proteins
  • Lipocalin-2
  • Lipocalins
  • Oncogene Proteins
  • PPAR gamma
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Lcn2 protein, mouse
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse

Grant support

This study was partly funded by the Swiss National Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.