LXR 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: 11.02). 08/2011; 109(5):492-501. DOI: 10.1161/CIRCRESAHA.111.241810
Source: PubMed


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.

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    • "C/EBP: CAAT/Enhancer binding protein, IL: Interleukin, IRF: Interferon Regulatory Factor, KLF4: Krü ppel-like factor 4, LXR: Liver X Receptor, PPAR: Peroxisome Proliferator-Activated Receptor, PR: Progesterone Receptor, P: Phosphate, PU.1: Purine box factor 1, RonRTK: Ron Receptor Tyrosine Kinase, RXR: Retinoid X Receptor, STAT: Signal Transducer and Activator of Transcription, Ub: Ubiquitin, VDR: Vitamin D Receptor. (1) (Odegaard et al., 2007), (2) (Odegaard et al., 2008), (3) (Pauleau et al., 2004), (4) (Qualls et al., 2010), (5) (Gray et al., 2005), (6) (Ye et al., 2012), (7) (Liao et al., 2011), (8) (Pourcet et al., 2011), (9) (Sharda et al., 2011), (10) (Hanna et al., 2012), (11) (Ehrchen et al., 2007). "
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    ABSTRACT: Atherosclerosis results from a metabolic imbalance and chronic arterial inflammation and macrophages are key during the initiation and progression of atherosclerotic lesions. A number of macrophage subsets have been identified in atherosclerotic plaques. Arginase 1 (Arg1), a marker for the M2 anti-inflammatory subset, hydrolyzes l-arginine into urea and ornithine, a precursor to l-proline and polyamines, which are implicated in tissue repair and wound healing. Additionally, Arg1 inhibits nitric oxide-mediated inflammatory pathways by competing with iNOS for the same substrate, l-arginine. Therefore, changes in Arg1 expression in macrophages may affect the development of atherosclerosis. Here, we present an overview of the transcriptional regulation of macrophage Arg1, focusing on the nuclear receptor family of ligand-activated transcription factors, and the relevance of this regulation to atherosclerosis.
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    • "Given the fact that PPARs can induce LXR expression and that LXRα expression was significantly increased in the WT recipients (Trogan et al., 2006), we wondered whether there would be a relationship between LXR and the M2 phenotype. We recently reported a molecular mechanism linking LXRα to the regulation of argI via purine box factor 1 (PU.1) and interferon regulatory factor 8 (IRF8) transcription factors (Pourcet et al., 2011). "
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    • "Moreover, no endogenous apoE production has been found in the J774 as well as in the RAW cells [21-23], whereas macrophage-apoE has been shown to significantly impact in vivo RCT [24]. Importantly, the responsiveness of RAW cells to liver X receptor (LXR) activation, one of the strongest stimuli of cholesterol efflux, is severely impaired due to a significant reduction in the expression of LXRβ and almost absent expression of LXRα [25,26]. In addition, the majority of the reported macrophage-to-feces RCT experiments are conducted in mice on a C57BL/6 background, while J774 and RAW 264.7 cells originate from BALB/c mice, and P388D1 cells were originally derived from DBA/2 mice. "
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    ABSTRACT: Plasma levels of high density lipoprotein (HDL) cholesterol are strongly inversely correlated to the risk of atherosclerotic cardiovascular disease. A major recognized functional property of HDL particles is to elicit cholesterol efflux and consequently mediate reverse cholesterol transport (RCT). The recent introduction of a surrogate method aiming at determining specifically RCT from the macrophage compartment has facilitated research on the different components and pathways relevant for RCT. The current review provides a comprehensive overview of studies carried out on macrophage-specific RCT including a quick reference guide of available data. Knowledge and insights gained on the regulation of the RCT pathway are summarized. A discussion of methodological issues as well as of the respective relevance of specific pathways for RCT is also included.
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