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Circ Res. 2011 Aug 19;109(5):492-501. doi: 10.1161/CIRCRESAHA.111.241810. Epub 2011 Jul 14.

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

Author information

1
Centre for Clinical Pharmacology, Division of Medicine, University College London, London, United Kingdom.

Abstract

RATIONALE:

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.

OBJECTIVE:

To investigate LXRα regulation of Arg1 expression in cultured macrophages and atherosclerotic regressive lesions.

METHODS AND RESULTS:

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.

CONCLUSIONS:

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.

PMID:
21757649
PMCID:
PMC3180895
DOI:
10.1161/CIRCRESAHA.111.241810
[Indexed for MEDLINE]
Free PMC Article

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