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

J Exp Med. 2010 Aug 2;207(8):1599-608. doi: 10.1084/jem.20091663. Epub 2010 Jul 12.

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

  • GW0742
  • 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
  • Interferon-gamma