Bone marrow-specific deficiency of nuclear receptor nur77 enhances atherosclerosis

A.A. Hamers, M. Vos, F. Rassam, G. Marinkovic, K. Kurakula, P.J. van Gorp, M.P. de Winther, M.J. Gijbels, V. de Waard, C.J. de Vries

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Abstract

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, IFNgamma, and SDF-1alpha and increased NO synthesis in (non)-stimulated Nur77(-/-) BMM cells. SDF-1alpha expression in nonstimulated Nur77(-/-) BMM is repressed by Nur77 and the chemoattractive activity of Nur77(-/-) BMM is abolished by SDF-1alpha 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-1alpha 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-1alpha expression and inhibits atherosclerosis.
Original languageEnglish
Pages (from-to)428-38
JournalCirculation Research
Volume110
Issue number3
DOIs
Publication statusPublished - 1 Jan 2012

Cite this

Hamers, A. A., Vos, M., Rassam, F., Marinkovic, G., Kurakula, K., van Gorp, P. J., de Winther, M. P., Gijbels, M. J., de Waard, V., & de Vries, C. J. (2012). Bone marrow-specific deficiency of nuclear receptor nur77 enhances atherosclerosis. Circulation Research, 110(3), 428-38. https://doi.org/10.1161/CIRCRESAHA.111.260760