NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis.

Abstract

RATIONALE:

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.

METHODS AND 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: Richard N Hanna, Iftach Shaked, Harper G Hubbeling, Jennifer A Punt, Runpei Wu, Erica Herrley, Claudia Zaugg, Hong Pei, Frederic Geissmann, Klaus Ley, Catherine C Hedrick
• Journal: Circulation research (Circ Res) Vol. 110 Issue 3 Pg. 416-27 (Feb 03 2012) ISSN: 1524-4571 [Electronic] United States
• PMID: 22194622 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• NF-kappa B
• Nr4a1 protein, mouse
• Nuclear Receptor Subfamily 4, Group A, Member 1
• Receptors, LDL
• Toll-Like Receptors

Topics

• Animals
• Apolipoproteins E (deficiency, genetics, physiology)
• Atherosclerosis (etiology, pathology, physiopathology)
• Diet (adverse effects)
• Disease Models, Animal
• Gene Deletion
• Humans
• Inflammation (pathology, physiopathology)
• Lipid Metabolism (physiology)
• Macrophages (pathology, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (physiology)
• Nuclear Receptor Subfamily 4, Group A, Member 1 (deficiency, genetics, physiology)
• Phenotype
• Receptors, LDL (deficiency, genetics, physiology)
• Toll-Like Receptors (physiology)