title: Bone marrow-specific deficiency of nuclear receptor Nur77 enhances atherosclerosis.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Anouk A J
authors.initials: AA
authors.lastname: Hamers
authors.forename: Mariska
authors.initials: M
authors.lastname: Vos
authors.forename: Fadi
authors.initials: F
authors.lastname: Rassam
authors.forename: Goran
authors.initials: G
authors.lastname: Marinković
authors.forename: Goran
authors.initials: G
authors.lastname: Marincovic
authors.forename: Kondababu
authors.initials: K
authors.lastname: Kurakula
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: van Gorp
authors.forename: Menno P J
authors.initials: MP
authors.lastname: de Winther
authors.forename: Marion J J
authors.initials: MJ
authors.lastname: Gijbels
authors.forename: Vivian
authors.initials: V
authors.lastname: de Waard
authors.forename: Carlie J M
authors.initials: CJ
authors.lastname: de Vries
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D016207:Cytokines; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D002784:Cholesterol