Foamy monocytes form early and contribute to nascent atherosclerosis in mice with hypercholesterolemia

Arterioscler Thromb Vasc Biol. 2015 Aug;35(8):1787-97. doi: 10.1161/ATVBAHA.115.305609. Epub 2015 Jun 25.


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

Approach and results: 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.

Conclusions: 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.

Keywords: atherosclerosis; diet, high-fat; inflammation; lipoproteins; monocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / drug effects
  • Aorta / immunology
  • Aorta / metabolism
  • Aorta / pathology*
  • Aortic Diseases / genetics
  • Aortic Diseases / immunology
  • Aortic Diseases / metabolism*
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atherosclerosis / genetics
  • Atherosclerosis / immunology
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control
  • CD11c Antigen / genetics
  • CD36 Antigens / deficiency
  • CD36 Antigens / genetics
  • Cell Line
  • Cholesterol, Dietary
  • Cholesterol, VLDL / metabolism*
  • Diet, High-Fat
  • Disease Models, Animal
  • Humans
  • Hypercholesterolemia / drug therapy
  • Hypercholesterolemia / genetics
  • Hypercholesterolemia / immunology
  • Hypercholesterolemia / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / drug effects
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Time Factors
  • Toll-Like Receptor 4 / deficiency
  • Toll-Like Receptor 4 / genetics


  • Apolipoproteins E
  • CD11c Antigen
  • CD36 Antigens
  • Cholesterol, Dietary
  • Cholesterol, VLDL
  • Receptors, LDL
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4