Article

NR4A1 (Nur77) Deletion Polarizes Macrophages Toward an Inflammatory Phenotype and Increases Atherosclerosis

Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, CA 92037, USA.
Circulation Research (Impact Factor: 11.02). 12/2011; 110(3):416-27. DOI: 10.1161/CIRCRESAHA.111.253377
Source: PubMed

ABSTRACT

NR4A1 (Nur77) is a nuclear receptor that is expressed in macrophages and within atherosclerotic lesions, yet its function in atherosclerosis is unknown.
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.
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.
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.

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    • "An increasing number of evidence suggest that NR4A receptors are highly expressed in advanced atherosclerotic lesions and injury induced vasculature [27]. Additionally, Nur77 deficiency has recently been shown to promote the development of atherosclerotic lesions in Apo-E knockout mice fed with a high fat diet through modulating inflammatory responses in microphages [31], further implicating their important roles in vascular diseases. Since ET-1 is highly expressed in human atherosclerotic lesions [8] [9], it is speculated that Nur77 deficiency may cause a higher expression of ET-1 and this may partially contribute to the increased atherosclerotic formation in Nur77 knockout mice. "
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    • "The domain structure of NR4A1 is similar to other nuclear receptors, containing an N-terminal activating function-1 domain, a zinc finger DNA-binding domain and a C-terminal ligand-binding domain (16,17). NR4A1 is reported to have multiple biological functions, regulating cell proliferation, differentiation, apoptosis, development, metabolism and immunity (16,18–20). The receptor exerts these physiological functions through expression regulation, post-translational modification and subcellular localization (21). "
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