PLoS Pathogens (Jan 2014)

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

  • Parag Kundu,
  • Teo Wei Ling,
  • Agata Korecka,
  • Yinghui Li,
  • Rossana D'Arienzo,
  • Ralph M Bunte,
  • Thorsten Berger,
  • Velmurugesan Arulampalam,
  • Pierre Chambon,
  • Tak Wah Mak,
  • Walter Wahli,
  • Sven Pettersson

DOI
https://doi.org/10.1371/journal.ppat.1003887
Journal volume & issue
Vol. 10, no. 1
p. e1003887

Abstract

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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.