In
atherosclerosis, macrophages are important for intracellular
lipid accumulation and foam cell formation. Monocytes respond to
chemotactic factors,
cytokines, and macrophage
growth factors produced by vascular endothelial cells, smooth muscle cells, and infiltrated cells, by migrating from peripheral blood into the arterial intima and differentiating into macrophages in atherosclerotic lesions. Although various
chemotactic factors are known to induce monocyte migration,
monocyte chemoattractant protein-1 is the most important and powerful inducer of migration into atherosclerotic lesions.
Macrophage colony-stimulating factor is crucial for monocyte/macrophage differentiation and proliferation, and for the survival of macrophages in these lesions. A minor population of macrophages can proliferate in the atherosclerotic lesions themselves, particularly in the early stage. The macrophages express a variety of receptors, particularly
scavenger receptors, and take up modified
lipoproteins, including
oxidized low-density lipoprotein,
beta-very-low-density lipoprotein, and/or enzymatically degraded
low-density lipoprotein. These cells accumulate
cholesterol esters in the cytoplasm, which leads to foam cell formation in lesion development. Among various
scavenger receptors, class A type I and type II
macrophage scavenger receptors (MSR-A I,II) play the most important role in the uptake of
oxidized low-density lipoprotein by macrophages. In addition, macrophages and macrophage-derived foam cells produce
ceroid and
advanced glycation end-products (AGEs) and accumulate these substances in their cytoplasm. Extracellularly generated AGEs are taken up by macrophages via receptors for AGEs, including MSR-AI,II. Most foam cells die in loco because of apoptosis, and some foam cells escape from the lesions into peripheral blood. Macrophages also play multifaceted roles in inducing plaque
rupture, blood coagulation, and fibrinolysis via the production of various
enzymes, activators, inhibitors, and bioactive mediators. During the development of
atherosclerosis, macrophages interact with vascular endothelial cells, medial smooth muscle cells, and infiltrated inflammatory cells, particularly T cells and dendritic cells. This review, based on data accumulated in studies of
atherosclerosis in humans and experimental animals, focuses on the multifunctional roles of macrophages in the pathogenesis and progression of
atherosclerosis.