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bioRxiv · 10.1101/2025.08.12.669996

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

Miller, Y. I.·Li, S.·Nazarenkov, N.·Alekseeva, E.·Navia-Pelaez, J. M.·Secrest, P.·Gordts, P. L.·Heinz, S.
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Abstract

Atherosclerotic lesions comprise different populations of macrophages, including lipid-laden macrophage foam cells and non-foamy, inflammatory macrophages, which play distinct roles in disease progression. Non-foamy macrophages express higher levels of inflammarafts - enlarged, cholesterol-rich lipid rafts hosting assemblies of inflammatory receptors - compared to foam cells in atherosclerotic lesions of Ldlr-/-mice. Apolipoprotein A-I binding protein (AIBP) has been shown to control lipid raft dynamics. This study investigated the effect of systemic AIBP deficiency on inflammaraft expression in foam cells and non-foamy macrophages in atherosclerotic lesions of hypercholesterolemic mice. A larger number of foam cells, with increased neutral lipid accumulation, populated atherosclerotic lesions in Apoa1bp-/-Ldlr-/-mice compared to Ldlr-/- mice. Importantly, AIBP-deficient foam cells expressed higher levels of TLR4 dimers and lipid rafts (markers of inflammarafts) than control mice, accompanied by larger atherosclerotic lesions and larger necrotic cores compared to Ldlr-/-mice. In a model of foam cells, Apoa1bp-/- bone marrow-derived macrophages incubated with oxidized LDL had increased expression of inflammation- and atherosclerosis-related genes. These results indicate that AIBP deficiency is associated with a proinflammatory transition of foam cells in which increased lipid accumulation is paradoxically associated with an increased expression of inflammarafts and correlates with the development of advanced atherosclerotic plaques.

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Miller, Y. I., Li, S., Nazarenkov, N., Alekseeva, E., Navia-Pelaez, J. M., Secrest, P., Gordts, P. L., Heinz, S.. 2025-08-15. Increased atherosclerosis and expression of inflammarafts in macrophage foam cells in AIBP-deficient mice. https://doi.org/10.1101/2025.08.12.669996

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