Absence of Intestinal PPARγ Aggravates Acute Infectious Colitis in Mice through a Lipocalin-2–Dependent Pathway
| Autor: | Tak W. Mak, Yat Li, Agata Korecka, Pierre Chambon, Ralph M. Bunte, Walter Wahli, Sven Pettersson, Parag Kundu, Rossana D’Arienzo, Velmurugesan Arulampalam, Thorsten Berger, Teo Wei Ling |
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| Přispěvatelé: | Monack, Denise M., Lee Kong Chian School of Medicine (LKCMedicine) |
| Rok vydání: | 2014 |
| Předmět: |
Salmonella typhimurium
QH301-705.5 Immunology Peroxisome proliferator-activated receptor Gastroenterology and Hepatology Biology Lipocalin Infectious Colitis Microbiology Cell Line Mice Lipocalin-2 Virology Genetics medicine Animals Humans Microbiome Biology (General) Colitis Receptor Science::General [DRNTU] Molecular Biology Immune Evasion Mice Knockout Oncogene Proteins chemistry.chemical_classification Innate immune system RC581-607 medicine.disease biology.organism_classification Lipocalins PPAR gamma Toll-Like Receptor 4 Matrix Metalloproteinase 9 chemistry Salmonella enterica Acute Disease Salmonella Infections Medicine Parasitology Immunologic diseases. Allergy Research Article Acute-Phase Proteins |
| Zdroj: | PLoS Pathogens PLoS Pathogens, vol. 10, no. 1, pp. e1003887 PLoS Pathogens, Vol 10, Iss 1, p e1003887 (2014) |
| ISSN: | 1553-7374 |
| Popis: | 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. Author Summary Enteric pathogens like S. Typhimurium convert the host intestine into an inflamed environment in which they are well adapted to thrive. However, the precise strategy that this pathogen employs to achieve such favorable conditions for its survival remains unclear. Here, we uncovered a novel mechanism whereby S. Typhimurium inhibits the expression of the transcription factor PPARγ in the host intestine, surprisingly without TLR-4 involvement; this inhibition worsened the severity of the host's colitis. Subsequent detailed analysis revealed that colitis severity was coupled with elevated levels of antimicrobials like Lcn2, which stabilized the pro-inflammatory endopeptidase MMP-9 in the intestinal milieu. Combination of this escalated antimicrobial action together with enhanced protease activity disrupted the intestinal homeostasis, promoting an inflamed environment suitable for S. Typhimurium. Interestingly, using Lcn2 mutant mice we show that lack of Lcn2 effectively reduced tissue damage and the degree of inflammation, thus supporting a pivotal role of Lcn2 and MMP-9 in infectious colitis. Our data suggests a model whereby the pathogenesis of S. Typhimurium involves manipulation of the host innate immune and protease system, here illustrated by PPARγ, Lcn2 and MMP-9, to establish colonization and infection within the host. |
| Databáze: | OpenAIRE |
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