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

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          Abstract

          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 clinical activity and colonic pathology, impaired the splenic and mesenteric lymph node regulatory T cell compartment, increased percentages of LP CD8+ T cells, increased surface expression of CD40, Ly6C, and TLR-4 in LP macrophages, and upregulated expression of colonic IFN-γ, CXCL9, CXCL10, IL-22, IL1RL1, CCR1, suppressor of cytokine signaling 3 and MCH class II in mice with IBD. Moreover, macrophage PPAR γ was required for accelerating pioglitazone-mediated recovery from DSS colitis, providing a cellular target for the anti-inflammatory effects of PPAR γ agonists in IBD.

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          Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance.

          Justin Odegaard, Roberto Ricardo-Gonzalez, Matthew H Goforth … (2007)
          Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.
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            Rosiglitazone for active ulcerative colitis: a randomized placebo-controlled trial.

            Daniel Present, J Deren, Bret A. Lashner … (2008)
            Thiazolidinedione ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARgamma), widely used to treat type 2 diabetes mellitus, have been proposed as novel therapies for ulcerative colitis (UC). This multicenter, randomized, double-blind, placebo-controlled clinical trial compared the efficacy of rosiglitazone (Avandia; GlaxoSmithKline, Philadelphia, PA) 4 mg orally twice daily vs placebo twice daily for 12 weeks in 105 patients with mild to moderately active UC. Disease activity was measured with the Mayo score. The primary end point was clinical response (>/=2-point reduction) at week 12. Clinical remission (Mayo score
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              Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein.

              Hannah Glass, L Fajas, Ronald A. Li … (1998)
              The peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that has been demonstrated to regulate fat cell development and glucose homeostasis. PPARgamma is also expressed in a subset of macrophages and negatively regulates the expression of several proinflammatory genes in response to natural and synthetic ligands. We here demonstrate that PPARgamma is expressed in macrophage foam cells of human atherosclerotic lesions, in a pattern that is highly correlated with that of oxidation-specific epitopes. Oxidized low density lipoprotein (oxLDL) and macrophage colony-stimulating factor, which are known to be present in atherosclerotic lesions, stimulated PPARgamma expression in primary macrophages and monocytic cell lines. PPARgamma mRNA expression was also induced in primary macrophages and THP-1 monocytic leukemia cells by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). Inhibition of protein kinase C blocked the induction of PPARgamma expression by TPA, but not by oxLDL, suggesting that more than one signaling pathway regulates PPARgamma expression in macrophages. TPA induced the expression of PPARgamma in RAW 264.7 macrophages by increasing transcription from the PPARgamma1 and PPARgamma3 promoters. In concert, these observations provide insights into the regulation of PPARgamma expression in activated macrophages and raise the possibility that PPARgamma ligands may influence the progression of atherosclerosis.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101299742
                Journal ID (pubmed-jr-id): 35518
                Journal ID (nlm-ta): Mucosal Immunol
                Journal ID (iso-abbrev): Mucosal Immunol
                Title: Mucosal immunology
                ISSN (Print): 1933-0219
                ISSN (Electronic): 1935-3456
                Publication date Nihms-submitted: 19 November 2010
                Publication date (Electronic): 10 November 2010
                Publication date (Print): May 2011
                Publication date PMC-release: 01 November 2011
                Volume: 4
                Issue: 3
                Pages: 304-313
                Affiliations
                Nutritional Immunology and Molecular Medicine Laboratory, CyberInfrastructure Division, Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, 24060, United States of America
                Author notes
                [* ]To whom correspondence should be addressed at: Dr. Josep Bassaganya-Riera, Laboratory of Nutritional Immunology & Molecular Medicine, Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061. Phone: (540) 231-7421, fax: (540) 231-2606, and jbassaga@ 123456vt.edu
                Article
                Manuscript ID: NIHMS253584
                DOI: 10.1038/mi.2010.75
                PMC ID: 3049196
                PubMed ID: 21068720
                SO-VID: 75f305e7-d00a-4ffb-904c-0126f72ed137
                History
                Funding
                Funded by: National Center for Complementary and Alternative Medicine : NCCAM
                Award ID: R01 AT004308-03 || AT
                Categories
                Subject: Article

                ScienceOpen disciplines: Immunology
                Data availability:
                ScienceOpen disciplines: Immunology

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