Absence of intestinal PPARγ aggravates acute infectious colitis in mice through a lipocalin-2-dependent pathway.
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.
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden ; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
Parag
P
Kundu
National Cancer Centre, Singapore.
Teo Wei
TW
Ling
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
Agata
A
Korecka
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
Yinghui
Y
Li
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
Rossana
R
D'Arienzo
Duke-NUS Graduate Medical School, Singapore.
Ralph M
RM
Bunte
Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Thorsten
T
Berger
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
Velmurugesan
V
Arulampalam
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, Inserm U964, Illkirch, France.
Pierre
P
Chambon
Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Tak Wah
TW
Mak
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore ; Center for Integrative Genomics, NCCR Frontiers in Genetics, University of Lausanne, Lausanne, Le Génopode, Switzerland.
Walter
W
Wahli
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden ; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore ; National Cancer Centre, Singapore.
Sven
S
Pettersson
D000208:Acute Disease; D000209:Acute-Phase Proteins / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D006801:Humans; D057131:Immune Evasion; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D047495:PPAR gamma / Q000235:genetics / Q000276:immunology*; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D012486:Salmonella typhimurium / Q000276:immunology* / Q000472:pathogenicity; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
D000209:Acute-Phase Proteins; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D047495:PPAR gamma; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C071332:Lcn2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse