Peroxisome proliferator-activated receptor delta limits the expansion of pathogenic Th cells during central nervous system autoimmunity.

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.

• Authors: Shannon E Dunn, Roopa Bhat, Daniel S Straus, Raymond A Sobel, Robert Axtell, Amanda Johnson, Kim Nguyen, Lata Mukundan, Marina Moshkova, Jason C Dugas, Ajay Chawla, Lawrence Steinman
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 207 Issue 8 Pg. 1599-608 (Aug 02 2010) ISSN: 1540-9538 [Electronic] United States
• PMID: 20624891 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Animals
• Brain (immunology, pathology)
• CD4-Positive T-Lymphocytes (drug effects, immunology, metabolism, transplantation)
• Cell Proliferation
• Encephalomyelitis, Autoimmune, Experimental (immunology, metabolism, pathology)
• Female
• Gene Expression (immunology)
• Glycoproteins (immunology)
• Homeodomain Proteins (genetics)
• Humans
• Interferon-gamma (genetics, metabolism)
• Interleukin-12 (genetics, metabolism)
• Interleukin-17 (genetics, metabolism)
• Leukocytes, Mononuclear (drug effects, immunology, metabolism)
• Lipopolysaccharides (pharmacology)
• Lymphocyte Activation (immunology)
• Macrophages, Peritoneal (drug effects, immunology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myelin-Oligodendrocyte Glycoprotein
• Myeloid Cells (drug effects, immunology, metabolism)
• Nuclear Receptor Subfamily 1, Group F, Member 3 (genetics)
• PPAR delta (antagonists & inhibitors, metabolism)
• Peptide Fragments (immunology)
• Spinal Cord (immunology, pathology)
• T-Box Domain Proteins (genetics)
• T-Lymphocytes, Helper-Inducer (drug effects, immunology, pathology, transplantation)
• Th1 Cells (immunology, metabolism)
• Thiazoles (pharmacology)
• Tumor Necrosis Factor-alpha (genetics, metabolism)