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 lamina propria (LP) CD8+ T cells, increased surface expression of CD40, Ly6C, and Toll-like receptor 4 (TLR-4) in LP macrophages, and upregulated expression of colonic IFN-γ, CXCL9, CXCL10, IL-22, IL1RL1, CCR1, suppressor of cytokine signaling 3, and MHC class II in mice with IBD. Moreover, macrophage PPAR-γ was required for accelerating pioglitazone-mediated recovery from dextran sodium sulfate (DSS) colitis, providing a cellular target for the anti-inflammatory effects of PPAR-γ agonists in IBD.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology
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Anti-Inflammatory Agents / therapeutic use
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Cells, Cultured
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Colitis / chemically induced
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Colitis / drug therapy
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Colitis / immunology*
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Colon / pathology
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Computational Biology
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Dextran Sulfate / administration & dosage
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Disease Models, Animal
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Gene Expression Regulation / immunology
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Humans
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Immunomodulation
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Inflammatory Bowel Diseases / drug therapy
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Inflammatory Bowel Diseases / immunology*
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism*
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Macrophages / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Microarray Analysis
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Mucous Membrane / pathology
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PPAR gamma / antagonists & inhibitors
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PPAR gamma / genetics
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PPAR gamma / immunology
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PPAR gamma / metabolism*
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Pioglitazone
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / pathology
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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T-Lymphocytes, Regulatory / pathology
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Thiazolidinediones / pharmacology
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Thiazolidinediones / therapeutic use
Substances
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Anti-Inflammatory Agents
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PPAR gamma
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Thiazolidinediones
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Dextran Sulfate
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Pioglitazone