Bone Marrow–Specific Deficiency of Nuclear Receptor Nur77 Enhances Atherosclerosis
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.
- Received November 11, 2011.
- Revision received December 12, 2011.
- Accepted December 14, 2011.
- © 2011 American Heart Association, Inc.