To examine infiltration of blood foamy monocytes, containing intracellular lipid droplets, into early atherosclerotic lesions and its contribution to development of nascent atherosclerosis.

In apoE^–/– mice fed Western high-fat diet (WD), >10% of circulating monocytes became foamy monocytes at 3 days on WD and >20% of monocytes at 1 week. Foamy monocytes also formed early in blood of Ldlr^–/–Apobec1^–/– (LDb) mice on WD. Based on CD11c and CD36, mouse monocytes were categorized as CD11c^–CD36^–, CD11c^–CD36⁺, and CD11c⁺CD36⁺. The majority of foamy monocytes were CD11c⁺CD36⁺, whereas most nonfoamy monocytes were CD11c^–CD36^– or CD11c^–CD36⁺ in apoE^–/– mice on WD. In wild-type mice, CD11c⁺CD36⁺ and CD11c^–CD36⁺, but few CD11c^–CD36^–, monocytes took up cholesteryl ester–rich very low-density lipoproteins (CE-VLDLs) isolated from apoE^–/– mice on WD, and CE-VLDL uptake accelerated CD11c^–CD36⁺ to CD11c⁺CD36⁺ monocyte differentiation. Ablation of CD36 decreased monocyte uptake of CE-VLDLs. Intravenous injection of DiI-CE-VLDLs in apoE^–/– mice on WD specifically labeled CD11c⁺CD36⁺ foamy monocytes, which infiltrated into nascent atherosclerotic lesions and became CD11c⁺ cells that were selectively localized in atherosclerotic lesions. CD11c deficiency reduced foamy monocyte infiltration into atherosclerotic lesions. Specific and consistent depletion of foamy monocytes (for 3 weeks) by daily intravenous injections of low-dose clodrosome reduced development of nascent atherosclerosis.

Foamy monocytes, which form early in blood of mice with hypercholesterolemia, infiltrate into early atherosclerotic lesions in a CD11c-dependent manner and play crucial roles in nascent atherosclerosis development.