Abstract 3969: Over-expression of IL10 in Macrophages Ameliorates Atherosclerosis in LDLR−/− mice
Introduction Macrophage foam cell formation is one of the requisite initiating events in atherogenesis. Although we and others have shown IL10 to have anti-atherogenic properties, mechanistic details of its actions have been lacking. Utilizing a macrophage-specific retroviral vector that allows the expression of genes in macrophages in vivo through the transplantation of retrovirally transduced hematopoietic stem cells, we sought to determine if overexpression of IL10 in macrophages would influence foam cell formation and ultimately atherosclerosis.
Methods & results In vitro results showed that IL10 promoted both cholesterol uptake, by up-regulating CD36, SR-I and SR-II (2, 8, 2 fold, respectively), as well as cholesterol efflux, by increasing LXR-PPARγ-ABCA1/ABCG1 expression in macrophages. In vivo macrophage-specific transgenic expression of IL10 in LDLR−/− mice markedly reduced the atherosclerotic lesion area by 47% (p<0.05, n=7) in the aorta and by 67% (p<0.05, n=7) in the aortic sinus. This athero-protective role of IL10 was independent of circulating lipid level as there were no differences in either cholesterol or triglyceride levels between IL10Tg and control groups. The presence of cholesterol and neutral lipids, as determined by confocal microscopy, were substantially reduced in aortic lesions of IL10Tg mice. Moreover, IL10 overexpression inhibited expression of pro-inflammatory molecules (TNFα, MMP9, and TIMP1 by 2, 5 and 3 fold, respectively) and suppressed apoptosis in atherosclerotic lesions.
Conclusion Our in vitro and in vivo studies indicate that IL10 can mediate both the uptake of cholesterol from modified LDL and the efflux of stored cholesterol, and thus may facilitate the removal of harmful atherogenic lipoprotein molecules from the vessel wall. These characteristics along with its ability to suppress the expression of inflammatory molecules and apoptosis of foam cells make IL10 a potent anti-atherogenic agent.