Absence of Intestinal PPARγ Aggravates Acute Infectious Colitis in Mice through a Lipocalin-2–Dependent Pathway

PLoS Pathogens

Velmurugesan Arulampalam¹  Walter Wahli¹  Rossana D'Arienzo²  Parag Kundu²  Ralph M. Bunte²  Pierre Chambon²  Yinghui Li²  Thorsten Berger³  Tak Wah Mak⁴  Teo Wei Ling⁵  Sven Pettersson⁵  Agata Korecka⁶ 

[1] Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada;Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden;Duke-NUS Graduate Medical School, Singapore;Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, Inserm U964, Illkirch, France;Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore;National Cancer Centre, Singapore

关键词: Salmonella typhimurium;    Colon;    Colitis;    Gastrointestinal tract;    Epithelial cells;    Mouse models;    Cecum;    Immunoblotting;   

DOI  :  10.1371/journal.ppat.1003887

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY