The Role of Monocytes and Macrophages in Human Atherosclerosis, Plaque Neoangiogenesis, and Atherothrombosis

Abstract

Atherosclerosis is one of the leading causes of death and disability worldwide. It is a complex disease characterized by lipid accumulation within the arterial wall, inflammation, local neoangiogenesis, and apoptosis. Innate immune effectors, in particular monocytes and macrophages, play a pivotal role in atherosclerosis initiation and progression. Although most of available evidence on the role of monocytes and macrophages in atherosclerosis is derived from animal studies, a growing body of evidence elucidating the role of these mononuclear cell subtypes in human atherosclerosis is currently accumulating. A novel pathogenic role of monocytes and macrophages in terms of atherosclerosis initiation and progression, in particular concerning the role of these cell subsets in neovascularization, has been discovered. The aim of the present article is to review currently available evidence on the role of monocytes and macrophages in human atherosclerosis and in relation to plaque characteristics, such as plaque neoangiogenesis, and patients' prognosis and their potential role as biomarkers.

Figure 1

Summary of the main findings of human studies concerned with monocytes and macrophages and atherosclerosis. In subjects with high risk plaques, intermediate CD14^hiCD16⁺ monocytes are enriched in the circulation. Less evidence is available for osteogenic biomarker expressing CD14⁺BAP⁺OCN⁺ monocytes, which appear to be enriched in the peripheral blood of subjects with large necrotic cores within the plaque. On the other hand, in subjects with highly neovascularized plaques, classical CD14^hiCD16⁻ monocytes are reduced in the circulation, possibly due to the redistribution into the plaque. Monocytes are activated by OxLDL acting through pattern recognition receptors (PRR). The PRR most frequently implicated in human cardiovascular disease is TLR4. Monocytes locally differentiate into macrophages, which take up OxLDL by means of scavenging receptors. Cholesterol is then transported outside the cell through specialized transporters, including ABCA1. ABCA1 transports cholesterol to nascent HDLs. When cholesterol loading exceeds macrophage efflux capability, the macrophage turns into a foam cell. Human plaques are enriched with NF-kB-expressing macrophages.