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

• Main Authors: Bunte, Ralph M., Kundu, Parag, Ling, Teo Wei, Korecka, Agata, Li, Yinghui, D'Arienzo, Rossana, Berger, Thorsten, Arulampalam, Velmurugesan, Chambon, Pierre, Mak, Tak Wah, Wahli, Walter, Pettersson, Sven
• Other Authors: Monack, Denise M.
• Format: Article
• Language: English
• Published: 2014
• Subjects: DRNTU::Science::General
• Online Access: https://hdl.handle.net/10356/80010; http://hdl.handle.net/10220/18858
• Institution: Nanyang Technological University

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.