Interferon-β promotes macrophage foam cell formation by altering both cholesterol influx and efflux mechanisms

Foam cell formation is a crucial event in atherogenesis. While interferon-beta (IFN beta) is known to promote atherosclerosis in mice, studies on the role of IFN beta on foam cell formation are minimal and conflicting. We therefore extended these studies using both in vitro and in vivo approaches and examined IFN beta's function in macrophage foam cell formation. To do so, murine bone marrow-derived macrophages (BMDMs) and human monocyte-derived macrophages were loaded with acLDL overnight, followed by 6 h IFN beta co-treatment. This increased lipid content as measured by Oil red O staining. We next analyzed the lipid uptake pathways of IFN beta-stimulated BMDMs and observed increased endocytosis of Dif-acLDL as compared to controls. These effects were mediated via SR-A, as its gene expression was increased and inhibition of SR-A with Poly(I) blocked the IFN beta-induced increase in Oil red O staining and Dil-acLDL endocytosis. The IFN beta-induced increase in lipid content was also associated with decreased ApoA1-mediated cholesterol efflux, in response to decreased ABCA1 protein and gene expression. To validate our findings in vivo, LDLR-/- mice were put on chow or a high cholesterol diet for 10 weeks. 24 and 8 h before sacrifice mice were injected with IFN beta or PBS, after which thioglycollate-elicited peritoneal macrophages were collected and analyzed. In accordance with the in vitro data,. IFN beta increased lipid accumulation. In conclusion, our experimental data support the pro-atherogenic role of IFN beta, as we show that IFN beta promotes macrophage foam cell formation by increasing SR-A-mediated cholesterol influx and decreasing ABCA1-mediated efflux mechanisms. (C) 2015 Elsevier Ltd. All rights reserved.