Abstract
Objective: Allograft inflammatory factor-1 (Aif-1) is best characterized as a cytoplasmic protein involved in actin bundling and phagocytosis. We investigated Aif-1 function in macrophage biology and the pathogenesis of atherosclerosis. Hypothesis: Aif-1-mediated potentiation of NFκB signaling promotes key macrophage functions and supports characteristics of plaque stability. Methods: We generated apoE -/- and aif-1 -/- ; apoE -/- mice (SKO and DKO, respectively), fed them a high fat diet for 18 weeks, and analyzed lesion burden in en face aorta, aortic root, and brachiocephalic arteries (BCA). We used immunofluorescence to assess marker expression and FACS analysis for proliferation and efferocytosis. Results: Lesion burden was not significantly different in aortic roots (DKO vs. SKO; 1.385e+006 ± 2065 vs 1.957e+006 ± 558, total lesion area), BCAs (DKO vs. SKO; 63 vs.65, % of Oil red O staining) and en face aortas (9 vs. 10, % of Oil red O staining). On the other hand, aortic root lesions from DKO mice showed more necrosis (DKO vs. SKO; 0.65 vs 0.4) and decreased fibrous cap thickness (DKO vs. SKO; 0.3 vs. 0.45, p0.05 respectively) normalized to lesion size. We also observed less macrophage staining (DKO vs. SKO; 0.6 vs. 2.2 % area/aortic root) and increased apoptosis (14 vs. 6 %Tunel+ cells), which correlated with decreased lesional P-NFκB p65 (DKO vs. SKO; 4 vs. 7 +nuclei/aortic root) activation. In vitro , aif-1 -/- macrophages showed decreases in oxidative stress-induced survival (40 vs. 80%), phagocytosis (30-60% decrease in zymosan particle uptake) and efferocytosis (40 vs.60 %F4/80;Tamra double +ve cells), and interleukin-6 release (1.2 vs 3 ng/ml in conditioned media). Mechanistically, these increased key macrophage functions correlated with P-NFκB p65 activation, which was impaired in aif-1 -/- macrophages. Conclusion: Our in vivo and in vitro data point to an essential role of Aif-1, via NFκB activation, in support of key macrophage functions, including survival and efferocytosis, that limit necrotic core size and increase atherosclerotic plaque stability.
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