Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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The immunoregulatory effect of macrophage-specific PPAR gamma deficiency on experimental inflammatory bowel disease

ABSTRACT: Inflammatory bowel disease (IBD) is a condition characterized by severe intestinal inflammation and immune cell activation. The severity of the disease can be mitigated by compounds which activate peroxisome proliferator-activated receptor gamma (PPAR gamma), a receptor present widely in tissues involved in IBD pathogenesis. Our objective was to assess the affect of macrophage-specific deficiency of PPAR gamma on peripheral and colonic immune populations and colonic gene expression in experimental IBD. Macrophage-specific PPAR gamma-deficient mice (PPAR gamma flfl Lysozyme M Cre+) and control (PPAR gamma flfl Lysozyme M Cre-) littermates were treated with 2.5% dextran sodium sulfate (DSS) for 7 days. Disease activity was recorded daily and immune cell populations in the blood, spleen, mesenteric lymph nodes (MLN), and lamina propria were examined by flow cytometry. Colonic gene expression was assessed by real time PCR and microarray analyses. Our findings show that macrophage PPAR r-deficiency significantly exacerbates DSS inflammation. CD4+CD25+FoxP3+ regulatory T cells (T-regs) were significantly reduced in Cre+ mice, and MLN macrophages and CD40 expression were enhanced. There were significant differences in the number colonic macrophages between Cre+ and Cre- mice, but those from Cre+ mice expressed more CD40, Ly6C, and TLR-4. PPAR r-deficiency also increased the percent of CD8+ T cells in the lamina propria and enhanced colonic interferon gamma expression. Our findings indicate that macrophage PPAR gamma deficiency augments the severity of DSS colitis by reducing peripheral T-regs and increasing colonic macrophage activation and T cell inflammation. RNA from 3 PPAR gamma-deficient mice (PPAR gamma flfl; Lysozyme M Cre+) and 3 control (PPAR gamma flfl; Lysozyme M Cre-) littermates was processed and labeled according to the standard target labeling protocols. The samples were hybridized, stained, and scanned per standard Affymetrix protocols at the Virginia Bioinformatics Institute (VBI) core laboratory on Mouse 430 2.0 expression arrays (Affymetrix Inc., Santa Clara, CA).

ORGANISM(S): Mus musculus

SUBMITTER: Josep Bassaganya-Riera

PROVIDER: E-GEOD-23421 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Immunoregulatory mechanisms of macrophage PPAR-γ in mice with experimental inflammatory bowel disease.

Hontecillas R R Horne W T WT Climent M M Guri A J AJ Evans C C Zhang Y Y Sobral B W BW Bassaganya-Riera J J

Mucosal immunology 20101110 3

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is widely expressed in macrophages and has been identified as a putative target for the development of novel therapies against inflammatory bowel disease (IBD). Computational simulations identified macrophages as key targets for therapeutic interventions against IBD. This study aimed to characterize the mechanisms underlying the beneficial effects of macrophage PPAR-γ in IBD. Macrophage-specific PPAR-γ deletion significantly exacerbated clini ...[more]

PMID: 21068720

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Project description:Here we describe our unprecedented approach in proposing parsley (PAR) as a nutraceutical intervention in inflammatory bowel disease (IBD) using a mouse model of dextran sodium sulphate (DSS)-induced colitis, following a multi-integrated-omics analysis. PAR supplementation (n=7) significantly improved colon shortening and increased the disease activity index compared to the DSS group (n=7). The colonic transcriptome revealed the down-regulation of inflammatory cytokines, and the hepatic transcriptome and metabolome revealed the up-regulation of fatty acid synthesis genes, thereby improving body weight loss. Down-regulated cancer markers were observed in the hepatic transcriptome and proteome. A global plasma metabolite analysis indicated shifts in the citric cycle and urea cycle, implicating improved impaired glycolysis and oxidative stress. Our integration of three omics analyses highlighted the involvement of the methionine-recycling pathway and PARM-bM-^@M-^Ys role in decreasing the risk of IBD. This pioneering use of multi-integrated-omics in the evaluation of nutrientsM-bM-^@M-^Y effects on physiology is expected to be widely useful and informative, shaping the future of nutritional research. Here we describe our unprecedented approach in proposing parsley (PAR) as a nutraceutical intervention in inflammatory bowel disease (IBD) using a mouse model of dextran sodium sulphate (DSS)-induced colitis, following a multi-integrated-omics analysis. PAR supplementation (n=7) significantly improved colon shortening and increased the disease activity index compared to the DSS group (n=7). The colonic transcriptome revealed the down-regulation of inflammatory cytokines, and the hepatic transcriptome and metabolome revealed the up-regulation of fatty acid synthesis genes, thereby improving body weight loss. Down-regulated cancer markers were observed in the hepatic transcriptome and proteome. A global plasma metabolite analysis indicated shifts in the citric cycle and urea cycle, implicating improved impaired glycolysis and oxidative stress. Our integration of three omics analyses highlighted the involvement of the methionine-recycling pathway and PARM-bM-^@M-^Ys role in decreasing the risk of IBD. This pioneering use of multi-integrated-omics in the evaluation of nutrientsM-bM-^@M-^Y effects on physiology is expected to be widely useful and informative, shaping the future of nutritional research. Total hepatic and colonic RNA from each respective group were pooled (n=7). The microarray analysis was carried as out as described by Jia et al. 8 Mouse Genome 430 2.0 Array GeneChips (Affymetrix, Santa Clara, CA) containing over 30,000 gene probe sets were used for genome-wide expression profiling.

Dataset Information

The immunoregulatory effect of macrophage-specific PPAR gamma deficiency on experimental inflammatory bowel disease

Publications

Immunoregulatory mechanisms of macrophage PPAR-γ in mice with experimental inflammatory bowel disease.

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