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

Autor: Lawrence Steinman, Daniel S. Straus, Raymond A. Sobel, Kim Nguyen, Lata Mukundan, Shannon E. Dunn, Marina Moshkova, Jason C. Dugas, Roopa Bhat, Amanda Johnson, Robert L. Axtell, Ajay Chawla
Rok vydání: 2010
Předmět:
CD4-Positive T-Lymphocytes
Lipopolysaccharides
Male
medicine.medical_treatment
Gene Expression
Peroxisome proliferator-activated receptor
Lymphocyte Activation
Mice
0302 clinical medicine
Immunology and Allergy
Myeloid Cells
PPAR delta
Receptor
Mice
Knockout
chemistry.chemical_classification
0303 health sciences
Interleukin-17
Experimental autoimmune encephalomyelitis
Brain
T-Lymphocytes
Helper-Inducer
Nuclear Receptor Subfamily 1
Group F
Member 3
Interleukin-12
3. Good health
Cell biology
Cytokine
Spinal Cord
Interleukin 12
Female
Peroxisome proliferator-activated receptor delta
Interleukin 17
Encephalomyelitis
Autoimmune
Experimental
Immunology
Biology
Interferon-gamma
03 medical and health sciences
Immune system
medicine
Animals
Humans
Cell Proliferation
Glycoproteins
030304 developmental biology
Homeodomain Proteins
Tumor Necrosis Factor-alpha
Brief Definitive Report
Th1 Cells
medicine.disease
Peptide Fragments
Mice
Inbred C57BL
Thiazoles
chemistry
Leukocytes
Mononuclear
Macrophages
Peritoneal
Myelin-Oligodendrocyte Glycoprotein
T-Box Domain Proteins
030215 immunology
Zdroj: The Journal of Experimental Medicine
ISSN: 1540-9538
0022-1007
DOI: 10.1084/jem.20091663
Popis: 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.
Databáze: OpenAIRE
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