LXRα Regulates Macrophage Arginase 1 Through PU.1 and Interferon Regulatory Factor 8

Rationale: Activation of liver X receptors (LXRs) inhibits the progression of atherosclerosis and promotes regression of existing lesions. In addition, LXR alpha 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 LXR alpha 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 LXR alpha markedly enhances basal and interleukin-4-induced Arg1 mRNA and protein expression as well as promoter activity. This LXR alpha-enhanced Arg1 expression correlates with a reduction in nitric oxide levels. Moreover, Arg1 expression within regressive atherosclerotic plaques is LXR alpha-dependent, as enhanced expression of Arg1 in regressive lesions is impaired in LXR alpha-deficient CD68+ cells. LXR alpha 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 alpha regulation of Arg1 expression in macrophage cells. Finally, we demonstrate that LXR alpha 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 LXR alpha as a novel regulator of Arg1 and IRF8 in macrophages. Furthermore, it provides a unique molecular mechanism by which LXR alpha regulates macrophage target gene expression through PU.1 and IRF8. (Circ Res. 2011; 109: 492-501.)