Abstract
BackgroundPeroxisome proliferator-activated receptor γ (PPAR γ) 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 γ in T cells modulates immune cell distribution and colonic gene expression and the severity of experimental IBD.MethodsPPAR γ 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.ResultsThe deficiency of PPAR γ 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-1β, 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 γ in T cells.ConclusionsThe expression of PPAR γ 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.
Highlights
Peroxisome proliferator-activated receptor γ (PPAR γ) is a nuclear receptor whose activation has been shown to modulate macrophage and T cell-mediated inflammation
The role of PPAR γ in epithelial cells was examined by Adachi et al, who found that the deficiency of PPAR γ resulted in significantly worsened disease activity and enhanced levels of pro-inflammatory cytokines interleukin 6 (IL-6) and IL-1β following dextan sodium sulfate (DSS)-induced colitis [11]
The loss of PPAR γ in T cells accelerates the onset of disease activity and body weight loss WT or CD4 Cre+ (CD4cre) mice were challenged with 2.5% DSS for 7 days to induce experimental Inflammatory bowel disease (IBD) and to determine the effect of T cell-specific deletion of PPAR γ on colitis severity, gene expression and immune cell distribution
Summary
Peroxisome proliferator-activated receptor γ (PPAR γ) is a nuclear receptor whose activation has been shown to modulate macrophage and T cell-mediated inflammation. PPAR γ is highly expressed in epithelial cells, Our laboratory has shown that the deficiency of PPAR γ in hematopoietic and epithelial cells significantly impairs the ability of a naturally occurring PPAR γ ligand, conjugated linoleic acid, to improve inflammatory bowel disease [2,8,9], or inflammation-driven colorectal cancer [10]. It remains unclear how these effects are mediated through macrophages, T cells, epithelial cells, or a combination of cells in the intestinal lamina propria, mesenteric lymph nodes (MLN) and circulating lymphocytes. The importance of T cell PPAR γ in the pathogenesis of IBD is less understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
