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Published on: April 21, 2015
The role of T cell PPAR gamma in mice with experimental inflammatory bowel disease
Amir J Guri1, Saroj K Mohapatra, William T Horne
1Nutritional Immunology and Molecular Nutrition Laboratory, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
Background:
Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been shown to modulate macrophage and T cell-mediated inflammation. The objective of this study was to investigate the mechanisms by which the deletion of PPAR gamma in T cells modulates immune cell distribution and colonic gene expression and the severity of experimental IBD.
Methods:
PPAR gamma flfl; CD4 Cre+ (CD4cre) or Cre- (WT) mice were challenged with 2.5% dextran sodium sulfate in their drinking water for 0, 2, or 7 days. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to assess lymphocyte and macrophage populations in the blood, spleen, and mesenteric lymph nodes (MLN). Global gene expression in colonic mucosa was profiled using Affymetrix microarrays.
Results:
The deficiency of PPAR gamma in T cells accelerated the onset of disease and body weight loss. Examination of colon histopathology revealed significantly greater epithelial erosion, leukocyte infiltration, and mucosal thickening in the CD4cre mice on day 7. CD4cre mice had more CD8+ T cells than WT mice and fewer CD4+ FoxP3+ regulatory T cells (Treg) and IL10+ CD4+ T cells in blood and MLN, respectively. Transcriptomic profiling revealed around 3000 genes being transcriptionally altered as a result of DSS challenge in CD4cre mice. These included up-regulated mRNA expression of adhesion molecules, proinflammatory cytokines interleukin-6 (IL-6) and IL-1beta, and suppressor of cytokine signaling 3 (SOCS-3) on day 7. Gene set enrichment analysis (GSEA) showed that the ribosome and Krebs cycle pathways were downregulated while the apoptosis pathway was upregulated in colons of mice lacking PPAR gamma in T cells.
Conclusions:
The expression of PPAR gamma in T cells is involved in preventing gut inflammation by regulating colonic expression of adhesion molecules and inflammatory mediators at later stages of disease while favoring the recruitment of Treg to the mucosal inductive sites.
Insights
T-cell specific deletion of Peroxisome proliferator-activated receptor gamma (PPAR gamma) exacerbates experimental inflammatory bowel disease (IBD). This PPAR gamma deficiency in T cells alters immune cell distribution and colonic gene expression, worsening gut inflammation.
Area of Science:
- Immunology
- Molecular Biology
- Gastroenterology
Background:
- Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor that modulates T cell and macrophage-mediated inflammation.
- Understanding the role of PPAR gamma in T cells is crucial for developing targeted therapies for inflammatory bowel disease (IBD).
Purpose of the Study:
- To investigate how deleting PPAR gamma in T cells affects immune cell distribution, colonic gene expression, and the severity of experimental IBD.
- To elucidate the specific mechanisms by which T-cell PPAR gamma influences the inflammatory response in the gut.
Main Methods:
- Mice with T-cell specific PPAR gamma deficiency (CD4cre) and wild-type (WT) littermates were subjected to dextran sodium sulfate (DSS)-induced colitis.
- Disease severity was assessed clinically and histopathologically.
- Immune cell populations were analyzed using flow cytometry, and colonic gene expression was profiled using microarrays.
Main Results:
- T-cell PPAR gamma deficiency accelerated disease onset and worsened clinical and histopathological outcomes in DSS-treated mice.
- Deficiency led to altered T cell populations, with fewer regulatory T cells (Treg) and IL-10+ CD4+ T cells.
- Colonic transcriptomic analysis revealed significant alterations in genes related to inflammation, adhesion molecules, and apoptosis.
Conclusions:
- PPAR gamma expression in T cells plays a protective role in experimental IBD.
- T-cell PPAR gamma regulates the expression of inflammatory mediators and adhesion molecules.
- It also influences the recruitment of regulatory T cells to the gut mucosa.
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