Abstract
Peroxisome proliferator-activated receptors (PPARs; PPAR-alpha, PPAR-delta, and PPAR-gamma) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-delta, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR-delta (PPAR-delta(-/-)) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN-gamma(+)IL-17A(-) and IFN-gamma(+)IL-17A(+) CD4(+) cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR-delta(-/-) mice occurred as a result of a constellation of immune system aberrations that included higher CD4(+) cell proliferation, cytokine production, and T-bet expression and enhanced expression of IL-12 family cytokines by myeloid cells. We also show that the effect of PPAR-delta in inhibiting the production of IFN-gamma and IL-12 family cytokines is ligand dependent and is observed in both mouse and human immune cells. Collectively, these findings suggest that PPAR-delta serves as an important molecular brake for the control of autoimmune inflammation.
Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- Animals
- Brain / immunology
- Brain / pathology
- CD4-Positive T-Lymphocytes / drug effects
- CD4-Positive T-Lymphocytes / immunology
- CD4-Positive T-Lymphocytes / metabolism
- CD4-Positive T-Lymphocytes / transplantation
- Cell Proliferation
- Encephalomyelitis, Autoimmune, Experimental / immunology*
- Encephalomyelitis, Autoimmune, Experimental / metabolism
- Encephalomyelitis, Autoimmune, Experimental / pathology*
- Female
- Gene Expression / immunology
- Glycoproteins / immunology
- Homeodomain Proteins / genetics
- Humans
- Interferon-gamma / genetics
- Interferon-gamma / metabolism
- Interleukin-12 / genetics
- Interleukin-12 / metabolism
- Interleukin-17 / genetics
- Interleukin-17 / metabolism
- Leukocytes, Mononuclear / drug effects
- Leukocytes, Mononuclear / immunology
- Leukocytes, Mononuclear / metabolism
- Lipopolysaccharides / pharmacology
- Lymphocyte Activation / immunology
- Macrophages, Peritoneal / drug effects
- Macrophages, Peritoneal / immunology
- Macrophages, Peritoneal / metabolism
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Myelin-Oligodendrocyte Glycoprotein
- Myeloid Cells / drug effects
- Myeloid Cells / immunology
- Myeloid Cells / metabolism
- Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
- PPAR delta / antagonists & inhibitors
- PPAR delta / metabolism*
- Peptide Fragments / immunology
- Spinal Cord / immunology
- Spinal Cord / pathology
- T-Box Domain Proteins / genetics
- T-Lymphocytes, Helper-Inducer / drug effects
- T-Lymphocytes, Helper-Inducer / immunology
- T-Lymphocytes, Helper-Inducer / pathology*
- T-Lymphocytes, Helper-Inducer / transplantation
- Th1 Cells / immunology
- Th1 Cells / metabolism
- Thiazoles / pharmacology
- Tumor Necrosis Factor-alpha / genetics
- Tumor Necrosis Factor-alpha / metabolism
Substances
- Glycoproteins
- Homeodomain Proteins
- Interleukin-17
- Lipopolysaccharides
- Myelin-Oligodendrocyte Glycoprotein
- Nuclear Receptor Subfamily 1, Group F, Member 3
- PPAR delta
- Peptide Fragments
- T-Box Domain Proteins
- T-box transcription factor TBX21
- Thiazoles
- Tumor Necrosis Factor-alpha
- myelin oligodendrocyte glycoprotein (35-55)
- RAG-1 protein
- Interleukin-12
- (4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid
- Interferon-gamma