Seminar: Prof. Carlie J.M. de Vries

Nuclear Receptor Nur77 in inflammatory disease: atherosclerosis

Date:
21 March 2013 00:00 hrs.
Location:
Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289
Title:
Nuclear Receptor Nur77 in inflammatory disease: atherosclerosis
Speaker(s):

Prof. Carlie J.M. de Vries, Dept. of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands

 

Host(s):

Prof. Gosse Adema en Nina Karthaus, Dept. Tumor Immunology

21-03-2013 00:00:00Europe/AmsterdamNuclear Receptor Nur77 in inflammatory disease: atherosclerosis Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289Rimlsrimls@radboudumc.nl

Remarks / more information:

Vries, de CarlieNuclear receptorNur77, also known as NR4A1, TR3 or NGFI-B, is expressed in human atherosclerotic lesions in macrophages, endothelial cells, T cells and smooth muscle cells. Macrophages play a critical role in atherosclerosis and the function of Nur77 in lesion macrophages has not yet been investigated. We aimed to delineate the function of Nur77 in macrophages and to assess the effect of bone marrow-specific deficiency of Nur77 on atherosclerosis.

We investigated Nur77 in macrophage polarization using bone marrow-derived macrophages (BMM) from wild-type and Nur77-knockout (Nur77-/-)-mice. Nur77-/- BMM exhibit changed expression of M2-specific markers and an inflammatory M1-phenotype with enhanced expression of IL12, IFNg, and SDF-1α and increased NO synthesis in (non)-stimulated Nur77-/- BMM cells. SDF-1α expression in non-stimulated Nur77-/- BMM is repressed by Nur77 and the chemoattractive activity of Nur77-/- BMM is abolished by SDF-1α inhibiting antibodies. The effect of bone marrow-specific deficiency of Nur77 on atherosclerosis was studied in low density lipoprotein receptor-deficient (Ldlr-/-) mice. Ldlr-/- mice with a Nur77-/--deficient bone marrow transplant develop larger atherosclerotic lesions than wild-type bone marrow transplanted mice. These lesions contain more macrophages, T cells, smooth muscle cells and larger necrotic cores. SDF-1α expression is higher in lesions of Nur77-/--transplanted mice, which may explain the observed aggravation of lesion formation.

In conclusion, in bone-marrow derived cells the nuclear receptor Nur77 has an anti-inflammatory function, represses SDF-1α expression and inhibits atherosclerosis.



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