| First Author | Pourcet B | Year | 2011 |
| Journal | Circ Res | Volume | 109 |
| Issue | 5 | Pages | 492-501 |
| PubMed ID | 21757649 | Mgi Jnum | J:186595 |
| Mgi Id | MGI:5432673 | Doi | 10.1161/CIRCRESAHA.111.241810 |
| Citation | Pourcet B, et al. (2011) LXRalpha regulates macrophage arginase 1 through PU.1 and interferon regulatory factor 8. Circ Res 109(5):492-501 |
| abstractText | RATIONALE: Activation of liver X receptors (LXRs) inhibits the progression of atherosclerosis and promotes regression of existing lesions. In addition, LXRalpha 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 LXRalpha 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 LXRalpha markedly enhances basal and interleukin-4-induced Arg1 mRNA and protein expression as well as promoter activity. This LXRalpha-enhanced Arg1 expression correlates with a reduction in nitric oxide levels. Moreover, Arg1 expression within regressive atherosclerotic plaques is LXRalpha-dependent, as enhanced expression of Arg1 in regressive lesions is impaired in LXRalpha-deficient CD68+ cells. LXRalpha 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 LXRalpha regulation of Arg1 expression in macrophage cells. Finally, we demonstrate that LXRalpha 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 LXRalpha as a novel regulator of Arg1 and IRF8 in macrophages. Furthermore, it provides a unique molecular mechanism by which LXRalpha regulates macrophage target gene expression through PU.1 and IRF8. |
