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

• Published in: The Journal of experimental medicine 2010-08, Vol.207 (8), p.1599-1608
• Main Authors: Dunn, Shannon E, Bhat, Roopa, Straus, Daniel S, Sobel, Raymond A, Axtell, Robert, Johnson, Amanda, Nguyen, Kim, Mukundan, Lata, Moshkova, Marina, Dugas, Jason C, Chawla, Ajay, Steinman, Lawrence
• Format: Article
• Language: English
• Subjects: Animals; Brain - immunology; Brain - pathology; Brief Definitive Report; 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; Peptide Fragments - immunology; PPAR delta - antagonists & inhibitors; PPAR delta - metabolism; 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
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20091663

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.