Increased atherosclerosis and expression of inflammarafts in macrophage foam cells in AIBP-deficient mice

Abstract Background Atherosclerotic lesions comprise different populations of macrophages, including lipid-laden macrophage foam cells and non-foamy, inflammatory macrophages, playing different roles in disease progression. Previous studies demonstrated higher expression of inflammarafts – enlarged, cholesterol-rich lipid rafts hosting assemblies of inflammatory receptors – in non-foamy, inflammatory macrophages, as opposed to lower inflammarafts in lipid-lade macrophage foam cells. Apolipoprotein A-I Binding Protein (AIBP) facilitates cholesterol efflux from macrophages and has been shown to reduce inflammatory responses and protect against atherosclerosis. This study investigated the effect of AIBP deficiency on inflammaraft expression in aortic foam cells and non-foamy macrophages in hypercholesterolemic mice. Methods Single-cell suspensions were prepared from aortae of Apoa1bp -/- Ldlr -/- and Ldlr -/- male and female mice fed a high-cholesterol, high-fat diet. CD45 + F4/80 + macrophages were gated for BODIPY-high foamy and BODIPY-low non-foamy cells and analyzed for the expression of inflammaraft markers TLR4 (toll-like receptor-4) dimers and lipid rafts. Consecutive sections of the aortic root were stained with modified Van Gieson stain to assess lesion and necrotic core sizes. Results Foam cells constituted a higher percentage of macrophages and contained more neutral lipid in Apoa1bp -/- Ldlr -/- compared to Ldlr -/- aorta. Importantly, in AIBP-deficient mice, foam cells expressed higher levels of TLR4 dimers and lipid rafts than in control mice, while non-foamy cells expressed similar levels. Apoa1bp -/- Ldlr -/- mice had larger atherosclerotic lesions and necrotic cores compared to Ldlr -/- mice. Male and female mice showed similar results. Conclusions Our results indicate that AIBP deficiency leads to the formation of a new foam cell phenotype in which the increased lipid accumulation is associated with an increased expression of TLR4 inflammarafts. This transition of foam cells to a proinflammatory phenotype correlates with the development of advanced atherosclerotic plaques.