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

ABSTRACT: Activation of liver X receptors (LXRs) inhibits the progression of atherosclerosis and promotes regression of existing lesions. In addition, LXR? 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 LXR? 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 LXR? markedly enhances basal and interleukin-4-induced Arg1 mRNA and protein expression as well as promoter activity. This LXR?-enhanced Arg1 expression correlates with a reduction in nitric oxide levels. Moreover, Arg1 expression within regressive atherosclerotic plaques is LXR?-dependent, as enhanced expression of Arg1 in regressive lesions is impaired in LXR?-deficient CD68+ cells. LXR? 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 LXR? regulation of Arg1 expression in macrophage cells. Finally, we demonstrate that LXR? 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 LXR? as a novel regulator of Arg1 and IRF8 in macrophages. Furthermore, it provides a unique molecular mechanism by which LXR? regulates macrophage target gene expression through PU.1 and IRF8.

SUBMITTER: Pourcet B 

PROVIDER: S-EPMC3180895 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature