Foamy Monocytes Form Early and Contribute to Nascent Atherosclerosis in Mice With Hypercholesterolemia

Abstract

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.

Foamy Monocytes Are Enriched in cis -7-Hexadecenoic Fatty Acid (16:1n-9), a Possible Biomarker for Early Detection of Cardiovascular Disease

“…While the role of circulating monocytes as precursors of macrophages, which after moving to the subendothelial space become foam cells, is clearly defined (Moore and Tabas, 2011;Tabas and Bornfeldt, 2016), our previous results support the emerging paradigm that monocytes interacting with proinflammatory products released by endothelial cells may acquire a foamy phenotype well before they cross the endothelial layer and differentiate into macrophages (Wu et al, 2009;Foster et al, 2015;Robbins et al, 2013;Xu et al, 2015). The accumulation of lipid droplets in the monocytes is accompanied by increased expression of adhesion and chemokine receptors and overall proinflammatory markers, resulting in a higher risk of cardiovascular disease.…”

“…The accumulation of lipid droplets in the monocytes is accompanied by increased expression of adhesion and chemokine receptors and overall proinflammatory markers, resulting in a higher risk of cardiovascular disease. Thus lipid droplets in circulating monocytes are being considered not only a possible therapeutic target, but also a marker of risk (Wu et al, 2009;Foster et al, 2015;Robbins et al, 2013;Xu et al, 2015). In this regard, our molecular analysis of the fatty acid composition of the neutral lipids of foamy monocytes revealed their selective enrichment in a relatively minor fatty acid, identified as palmitoleic acid (Guijas et al, 2012).…”

PCSK9 inhibitors and foamy monocytes in familial hypercholesterolaemia

“…In another publication, the same research group reported that monocytes from patients with familial dysbetalipoproteinaemia (FD) also had increased intracellular lipid accumulation and higher expression of surface β 2 -integrins, including integrin-α M (CD11b), integrin-α X (CD11c), and integrin-β 2 (CD18) 5 . These observations support an important role of intracellular lipid accumulation in monocyte phenotypic changes in patients with FH or FD, and are consistent with previous reports from our laboratory and others showing emergence of monocytes with intracellular lipid droplets, which we termed ‘foamy monocytes’, and monocyte phenotypic changes including increased levels of integrin-α X in the circulation of humans and animals with hyperlipidaemia 6–9 . Foamy monocytes emerge early in the circulation of mice with hypercholesterolaemia 6 .…”

Macrophages and Dendritic Cells

“…Monocyte lipid uptake is dependent on CD36 and is associated with upregulated expression of CD11c, chemokine receptors, and activation of CD49d (α4) integrin, which mediates adhesion to vascular cell adhesion molecule-1. [138][139][140][141] Monocytes with cytoplasmic lipid droplets can also be found in humans after a high-fat high-cholesterol meal, but the extent of intracellular lipid is much lower relative to mice. 139,140,142,143 The systemic effects of hyperlipidemia on circulating monocytes promote monocyte recruitment to atherosclerotic lesions.…”