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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
Absence of intestinal PPARγ aggravates acute infectious colitis in mice through a lipocalin-2-dependent pathway
Parag Kundu1, Teo Wei Ling2, Agata Korecka3
1Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden ; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
Abstract:
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.
Insights
Salmonella Typhimurium causes colitis by inhibiting peroxisome proliferator-activated receptor gamma (PPARγ) and increasing lipocalin-2 (Lcn2). Lcn2 deficiency protects mice from Salmonella-induced colitis.
Area of Science:
- Microbiology
- Immunology
- Gastroenterology
Background:
- Host-microbiome homeostasis is crucial for preventing pathogen invasion.
- Salmonella enterica serovar Typhimurium (S. Typhimurium) disrupts this balance to colonize hosts.
Purpose of the Study:
- To investigate the mechanism by which S. Typhimurium induces infectious colitis.
- To identify key host immune factors involved in S. Typhimurium pathogenesis.
Main Methods:
- Investigated the role of peroxisome proliferator-activated receptor gamma (PPARγ) in S. Typhimurium-induced colitis.
- Analyzed the expression of innate immune response genes, including lipocalin-2 (Lcn2).
- Utilized Lcn2-null mice to assess the impact of Lcn2 on colitis severity.
Main Results:
- S. Typhimurium inhibits PPARγ expression in intestinal epithelial cells, independent of TLR-4 signaling.
- This inhibition elevates innate immune genes, notably Lcn2, which stabilizes MMP-9 and worsens colitis.
- Lcn2-null mice showed significantly reduced colitis and protection during S. Typhimurium infection.
Conclusions:
- S. Typhimurium hijacks host immune gene regulation (PPARγ, Lcn2) for colonization.
- Lcn2 plays a critical role in exacerbating S. Typhimurium-induced colitis.
- Targeting Lcn2 may offer a therapeutic strategy against Salmonella infections.
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