LXRα regulates macrophage arginase 1 through PU.1 and interferon regulatory factor 8.

Centre for Clinical Pharmacology, Division of Medicine, University College London, London, United Kingdom.
Circulation Research (Impact Factor: 11.09). 08/2011; 109(5):492-501. DOI: 10.1161/CIRCRESAHA.111.241810
Source: PubMed

ABSTRACT Activation of liver X receptors (LXRs) inhibits the progression of atherosclerosis and promotes regression of existing lesions. In addition, LXRα levels are high in regressive plaques. Macrophage arginase 1 (Arg1) expression is inversely correlated with atherosclerosis progression and is markedly decreased in foam cells within the lesion.
To investigate LXRα regulation of Arg1 expression in cultured macrophages and atherosclerotic regressive lesions.
We found that Arg1 expression is enhanced in CD68+ cells from regressive versus progressive lesions in a murine aortic arch transplant model. In cultured macrophages, ligand-activated LXRα markedly enhances basal and interleukin-4-induced Arg1 mRNA and protein expression as well as promoter activity. This LXRα-enhanced Arg1 expression correlates with a reduction in nitric oxide levels. Moreover, Arg1 expression within regressive atherosclerotic plaques is LXRα-dependent, as enhanced expression of Arg1 in regressive lesions is impaired in LXRα-deficient CD68+ cells. LXRα does not bind to the Arg1 promoter but instead promotes the interaction between PU.1 and interferon regulatory factor (IRF)8 transcription factors and induces their binding of a novel composite element. Accordingly, knockdown of either IRF8 or PU.1 strongly impairs LXRα regulation of Arg1 expression in macrophage cells. Finally, we demonstrate that LXRα binds the IRF8 locus and its activation increases IRF8 mRNA and protein levels in these cells.
This work implicates Arg1 in atherosclerosis regression and identifies LXRα as a novel regulator of Arg1 and IRF8 in macrophages. Furthermore, it provides a unique molecular mechanism by which LXRα regulates macrophage target gene expression through PU.1 and IRF8.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hyperoxia exposure of premature infants causes obliteration of the immature retinal microvessels, leading to a condition of proliferative vitreoretinal neovascularization termed retinopathy of prematurity (ROP). Previous work has demonstrated that the hyperoxia-induced vascular injury is mediated by dysfunction of endothelial nitric oxide synthase resulting in peroxynitrite formation. This study was undertaken to determine the involvement of the ureahydrolase enzyme arginase in this pathology.
    PLoS ONE 11/2014; 9(11):e110604. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The interferon-regulatory factor (IRF) family comprises nine members in mammals. Although this transcription factor family was originally thought to function primarily in the immune system, contributing to both the innate immune response and the development of immune cells, recent advances have revealed that IRFs plays critical roles in other biological processes, such as metabolism. Accordingly, abnormalities in the expression and/or function of IRFs have increasingly been linked to disease. Herein, we provide an update on the recent progress regarding the regulation of immune responses and immune cell development associated with IRFs. Additionally, we discuss the relationships between IRFs and immunity, metabolism, and disease, with a particular focus on the role of IRFs as stress sensors. This article is part of a Special Issue entitled: From Genome to Function.
    Biochimica et Biophysica Acta 05/2014; · 4.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Interferon regulatory factor 8 (IRF8), a member of IRF transcription factor family, was recently implicated in vascular diseases. In the present study, using the mouse left carotid artery wire injury model, we unexpectedly observed that the expression of IRF8 was greatly enhanced in SMCs by injury. Compared with wild-type controls, IRF8 global knockout mice exhibited reduced neointimal lesions and maintained SMC-marker gene expression. We further generated SMC-specific IRF8 transgenic mice using an SM22α-driven IRF8 plasmid construct. In contrast to the knockout mice, the SMCs-overexpressing IRF8 exhibited a synthetic phenotype and enhanced neointima formation in the mice. Mechanistically, IRF8 inhibited SMC-marker gene expression through regulating serum response factor (SRF) transactivation in a myocardin-dependent manner. Furthermore, co-immunoprecipitation assay indicated a direct interaction of IRF8 with myocardin, in which a specific region of myocardin was essential for recruiting acetyltransferase p300. Altogether, IRF8 is crucial in modulating SMC phenotype switching and neointima formation in response to vascular injury via direct interaction with SRF/myocardin complex.
    Molecular and Cellular Biology 11/2013; · 5.04 Impact Factor

Full-text (2 Sources)

Available from
Jun 6, 2014