Bone Marrow–Specific Deficiency of Nuclear Receptor Nur77 Enhances Atherosclerosis

• Published in: Circulation research 2012-02, Vol.110 (3), p.428-438
• Main Authors: Hamers, Anouk A.J, Vos, Mariska, Rassam, Fadi, Marinković, Goran, Kurakula, Kondababu, van Gorp, Patrick J, de Winther, Menno P.J, Gijbels, Marion J.J, de Waard, Vivian, de Vries, Carlie J.M
• Format: Article
• Language: English
• Subjects: Animals; Atherosclerosis (general aspects, experimental research); Atherosclerosis - metabolism; Atherosclerosis - pathology; Atherosclerosis - physiopathology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Adhesion - physiology; Cell Movement - physiology; Cells, Cultured; Chemokine CXCL12 - metabolism; Cholesterol - metabolism; Cytokines - metabolism; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Inflammation - metabolism; Inflammation - pathology; Inflammation - physiopathology; Macrophages - metabolism; Macrophages - pathology; Macrophages - physiology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Receptor Subfamily 4, Group A, Member 1 - deficiency; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism; Phenotype; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.111.260760

RATIONALE:Nuclear receptor Nur77, 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. OBJECTIVE:This study aims to delineate the function of Nur77 in macrophages and to assess the effect of bone marrow–specific deficiency of Nur77 on atherosclerosis. METHODS AND RESULTS: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 interleukin-12, IFNγ, and SDF-1α and increased NO synthesis in (non)-stimulated Nur77 BMM cells. SDF-1α expression in nonstimulated Nur77 BMM is repressed by Nur77 and the chemoattractive activity of Nur77 BMM is abolished by SDF-1α inhibiting antibodies. Furthermore, Nur77 mice show enhanced thioglycollate-elicited migration of macrophages and B cells. 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 developed 2.1-fold 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. CONCLUSIONS:In conclusion, in bone marrow–derived cells the nuclear receptor Nur77 has an anti-inflammatory function, represses SDF-1α expression and inhibits atherosclerosis.