Interferon‐α priming promotes lipid uptake and macrophage‐derived foam cell formation: A novel link between interferon‐α and atherosclerosis in lupus

Abstract

Objective. An increased risk of premature atherosclerosis has been associated with systemic lupus erythematosus (SLE), and type I interferon (IFN) has been shown to play a pathogenic role in human SLE. The aim of this study was to determine whether IFN␣ is involved in the development of atherosclerosis in patients with SLE by promoting lipid uptake and macrophagederived foam cell formation, which is a crucial step in early atherosclerosis.Methods Results. IFN␣ priming increased the uptake of oxidized low-density lipoprotein and hence enhanced foam cell formation by up-regulating SR-A expression. IFN␣ increased SR-A expression via enhancing its promoter activities. Examination using signaling inhibitors revealed that a phosphatidylinositol 3-kinase/Akt signaling pathway appeared to be involved in this process. Notably, SR-A messenger RNA was significantly increased in patients with SLE compared to normal subjects and positively correlated with IFIG expression.Conclusion. Our data suggest that IFN␣ priming up-regulated the expression of SR-A in human monocyte/macrophages, leading to increased lipid uptake and foam cell formation. Activation of the IFN signaling pathway may be linked to the risk of atherosclerosis by affecting plaque formation in patients with SLE. These findings provide novel insights into the mechanisms of and potential therapeutic approaches to premature atherosclerosis in patients with SLE.

Coronary Heart Disease in Systemic Lupus Erythematosus Is Associated With Interferon Regulatory Factor-8 Gene Variants

“…38 In addition, IRF8 helps to prolong the recruitment of transcription factors to the interferon promoters and thereby amplifies the interferon production. 41 Because interferon-α via several different mechanisms 12,15,[42][43][44][45][46] is important in the development of atherosclerosis in SLE, 16 the IRF8 risk gene variants may contribute to the increased CHD incidence in SLE by affecting the function of the type I interferon system. This includes potential effects on pDCs and also B cells, which are dependent on IRF8 for differentiation and function.…”

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

“…Macrophages were incubated with Dil-labeled oxLDL, and the extent of cholesterol uptake was quantitated by fluorescence measurement, as previously reported 31,32) . Briefly, Dil-labeled oxLDL (10 g/mL, Yiyuan Biotech) was incubated with macrophages for 6 h at 37 .…”

MICA/B expression in macrophage foam cells infiltrating atherosclerotic plaques

“…Recent work has shown that exposure to high glucose in vitro enhances SR-A expression in human MDMs, accounting for the high incidence of atherosclerosis in diabetic patients (Fukuhara-Takaki et al, 2005). SR-A expression is also up-regulated by interferon-, providing a possible explanation for the high risk of atherosclerosis in patients with systemic lupus erythematosus (Li et al, 2011).…”