Immunoregulatory Actions of Epithelial Cell PPAR γ at the Colonic Mucosa of Mice with Experimental Inflammatory Bowel Disease

Abstract

BackgroundPeroxisome proliferator-activated receptors are nuclear receptors highly expressed in intestinal epithelial cells (IEC) and immune cells within the gut mucosa and are implicated in modulating inflammation and immune responses. The objective of this study was to investigate the effect of targeted deletion of PPAR γ in IEC on progression of experimental inflammatory bowel disease (IBD).Methodology/Principal FindingsIn the first phase, PPAR γ flfl; Villin Cre- (VC-) and PPAR γ flfl; Villin Cre+ (VC+) mice in a mixed FVB/C57BL/6 background were challenged with 2.5% dextran sodium sulfate (DSS) in drinking water for 0, 2, or 7 days. VC+ mice express a transgenic recombinase under the control of the Villin-Cre promoter that causes an IEC-specific deletion of PPAR γ. In the second phase, we generated VC- and VC+ mice in a C57BL/6 background that were challenged with 2.5% DSS. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to phenotypically characterize lymphocyte and macrophage populations in blood, spleen and mesenteric lymph nodes. Global gene expression analysis was profiled using Affymetrix microarrays. The IEC-specific deficiency of PPAR γ in mice with a mixed background worsened colonic inflammatory lesions, but had no effect on disease activity (DAI) or weight loss. In contrast, the IEC-specific PPAR γ null mice in C57BL/6 background exhibited more severe inflammatory lesions, DAI and weight loss in comparison to their littermates expressing PPAR γ in IEC. Global gene expression profiling revealed significantly down-regulated expression of lysosomal pathway genes and flow cytometry results demonstrated suppressed production of IL-10 by CD4+ T cells in mesenteric lymph nodes (MLN) of IEC-specific PPAR γ null mice.Conclusions/SignificanceOur results demonstrate that adequate expression of PPAR γ in IEC is required for the regulation of mucosal immune responses and prevention of experimental IBD, possibly by modulation of lysosomal and antigen presentation pathways.

Disruption of inducible 6-phosphofructo-2-kinase impairs the suppressive effect of PPARγ activation on diet-induced intestine inflammatory response

“…Because of this, it is conceivable that intact PFKFB3/iPFK2 is needed for PPARγ activation to suppress overnutrition-induced intestine inflammatory response. On the other hand, although PPARγ activation brought about an anti-inflammatory effect in intestine in a manner consistent with that reported previously [20,21], suppressing diet-induced adipose tissue inflammatory response may be a prerequisite for PPARγ activation to suppress diet-induced intestine inflammatory response, given the primary role played by adipose tissue in the actions of PPARγ activation. Indeed, failure of rosiglitazone in fully suppressing diet-induced intestine inflammatory response reported herein was accompanied by defects in actions of rosiglitazone on reserving adipose tissue inflammatory response in PFKFB3/iPFK2-disrupted mice [28].…”

“…PPARγ has a protective role in intestine inflammation [20,21]. The effects of PPARγ activation on diet-induced intestine inflammatory response were examined.…”

“…At this point, little is known about how glucose and lipid metabolism is orchestrated to regulate intestine inflammatory response. In terms of managing intestine inflammatory response, adequate expression of PPARγ in epithelial cells appears to be required for prevention of inflammatory bowel disease [20,21]. Given this, addressing the link between intestine nutrient metabolism and the anti-intestine-inflammatory effect of active PPARγ is of particular importance to a better understanding of the pathophysiology of overnutrition-associated insulin resistance and inflammatory intestine diseases.…”

ANGPTL4 expression induced by butyrate and rosiglitazone in human intestinal epithelial cells utilizes independent pathways

“…One of the postulated mechanisms of action is via ligand-activated transcription factors, such as members of the peroxisome proliferator-activated receptor (PPAR) family. In the intestinal epithelium, PPAR-␥ is the most studied PPAR isoform, and it is implicated in the regulation of fatty acid metabolism via ␤-oxidation and in cell proliferation (54), as well as in gut homeostasis (1,40). PPAR-␥ regulates ANGPTL4 expression (3,29), and a PPARresponsive element (PPRE) within the third intron of the ANGPTL4 gene in humans and mice was identified (28,38).…”

Protection by Enteral Glutamine is Mediated by Intestinal Epithelial Cell Peroxisome Proliferator–Activated Receptor-γ During Intestinal Ischemia/Reperfusion

“…(21,22) Mice with a targeted deletion of PPARγ in IEC had worsened parameters of colonic disease such as inflammatory lesions and diarrhea. To our knowledge, the current study is the first to examine IEC PPARγ in the small bowel and the first to demonstrate an increase in mortality with loss of IEC PPARγ after injury.…”