Peroxisome proliferator-activated receptor delta limits the expansion of pathogenic Th cells during central nervous system autoimmunity.
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.
Dunn
Shannon E
SE
Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA. sdunn@uhnresearch.ca
Bhat
Roopa
R
Straus
Daniel S
DS
Sobel
Raymond A
RA
Axtell
Robert
R
Johnson
Amanda
A
Nguyen
Kim
K
Mukundan
Lata
L
Moshkova
Marina
M
Dugas
Jason C
JC
Chawla
Ajay
A
Steinman
Lawrence
L
D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D049109:Cell Proliferation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics; D047494:PPAR delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010446:Peptide Fragments / Q000276:immunology; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D020825:T-Box Domain Proteins / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology / Q000473:pathology* / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000098815:T-bet Transcription Factor; D010636:Phenols; D013438:Sulfhydryl Compounds
D006023:Glycoproteins; D018398:Homeodomain Proteins; D007371:Interferon-gamma; D018664:Interleukin-12; D020381:Interleukin-17; D008070:Lipopolysaccharides; D063308:Myelin-Oligodendrocyte Glycoprotein; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D047494:PPAR delta; D010446:Peptide Fragments; D020825:T-Box Domain Proteins; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D000098815:T-bet Transcription Factor; C445081:myelin oligodendrocyte glycoprotein (35-55); C064658:RAG-1 protein; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds