title: NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis.
abstract: BACKGROUND
  NR4A1 (Nur77) is a nuclear receptor that is expressed in macrophages and within atherosclerotic lesions, yet its function in atherosclerosis is unknown.
  
  
  OBJECTIVE
  Nur77 regulates the development of monocytes, particularly patrolling Ly6C(-) monocytes that may be involved in resolution of inflammation. We sought to determine how absence of nuclear receptor subfamily 4, group A, member 1 (NR4A1) in hematopoietic cells affected atherosclerosis development.
  
  
  RESULTS
  Nur77(-/-) chimeric mice on a Ldlr(-/-) background showed a 3-fold increase in atherosclerosis development when fed a Western diet for 20 weeks, despite having a drastic reduction in Ly6C(-) patrolling monocytes. In a second model, mice deficient in both Nur77 and ApoE (ApoE(-/-)Nur77(-/-)) also showed increased atherosclerosis after 11 weeks of Western diet. Atherosclerosis was associated with a significant change in macrophage polarization toward a proinflammatory phenotype, with high expression of tumor necrosis factor-α and nitric oxide and low expression of Arginase-I. Moreover, we found increased expression of toll-like receptor 4 mRNA and protein in Nur77(-/-) macrophages as well as increased phosphorylation of the p65 subunit of NFκB. Inhibition of NFκB activity blocked excess activation of Nur77(-/-) macrophages.
  
  
  CONCLUSIONS
  We conclude that the absence of Nur77 in monocytes and macrophages results in enhanced toll-like receptor signaling and polarization of macrophages toward a proinflammatory M1 phenotype. Despite having fewer monocytes, Nur77(-/-) mice developed significant atherosclerosis when fed a Western diet. These studies indicate that Nur77 is a novel target for modulating the inflammatory phenotype of monocytes and macrophages and may be important for regulation of atherogenesis.
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, CA 92037, USA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Hanna
authors.forename: Iftach
authors.initials: I
authors.lastname: Shaked
authors.forename: Harper G
authors.initials: HG
authors.lastname: Hubbeling
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Punt
authors.forename: Runpei
authors.initials: R
authors.lastname: Wu
authors.forename: Erica
authors.initials: E
authors.lastname: Herrley
authors.forename: Claudia
authors.initials: C
authors.lastname: Zaugg
authors.forename: Hong
authors.initials: H
authors.lastname: Pei
authors.forename: Frederic
authors.initials: F
authors.lastname: Geissmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Hedrick
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation / Q000473:pathology* / Q000503:physiopathology; D050356:Lipid Metabolism / Q000502:physiology; D008264:Macrophages / Q000473:pathology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: D001057:Apolipoproteins E; D016328:NF-kappa B; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011973:Receptors, LDL; D051193:Toll-Like Receptors