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Review
. 2011 Jul;31(7):1506-16.
doi: 10.1161/ATVBAHA.110.221127.

Monocyte and macrophage dynamics during atherogenesis

Klaus Ley  1 , Yury I Miller, Catherine C Hedrick
Affiliations
Review

Monocyte and macrophage dynamics during atherogenesis

Klaus Ley et al. Arterioscler Thromb Vasc Biol. 2011 Jul.

Abstract

Vascular inflammation is associated with and in large part driven by changes in the leukocyte compartment of the vessel wall. Here, we focus on monocyte influx during atherosclerosis, the most common form of vascular inflammation. Although the arterial wall contains a large number of resident macrophages and some resident dendritic cells, atherosclerosis drives a rapid influx of inflammatory monocytes (Ly-6C(+) in mice) and other monocytes (Ly-6C(-) in mice, also known as patrolling monocytes). Once in the vessel wall, Ly-6C(+) monocytes differentiate to a phenotype consistent with inflammatory macrophages and inflammatory dendritic cells. The phenotype of these cells is modulated by lipid uptake, Toll-like receptor ligands, hematopoietic growth factors, cytokines, and chemokines. In addition to newly recruited macrophages, it is likely that resident macrophages also change their phenotype. Monocyte-derived inflammatory macrophages have a short half-life. After undergoing apoptosis, they may be taken up by surrounding macrophages or, if the phagocytic capacity is overwhelmed, can undergo secondary necrosis, a key event in forming the necrotic core of atherosclerotic lesions. In this review, we discuss these and other processes associated with monocytic cell dynamics in the vascular wall and their role in the initiation and progression of atherosclerosis.

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Figures

Figure 1
Figure 1. Monocyte recruitment to atherosclerotic lesions
Blood monocytes may be decorated with platelets through P-selectin-PSGL-1 interactions. They can also roll and adhere to platelets bound to von Willebrand Factor (vWF, blue multimers) secreted from endothelial cells. Monocyte arrest can be triggered by chemokines (colored bars) including CCL5/CXCL4 heterodimers, CXCL1, CXCL2 and (in humans) CXCL8. Arrested monocytes are thought to transmigrate into the lesion, where they differentiate to inflammatory macrophages (Mφ) and foam cells, which can undergo secondary necrosis to form the necrotic core in the neointima. Inflammatory macrophages may also migrate through the media (black lines represent laminae elasticae) to the adventitia. Monocytes may also be recruited to the adventitia through vasa vasorum. Resident macrophages (blue) and dendritic cells (green) are constitutively found in the adventitia and may be able to migrate between these two compartments (dashed arrow).
Figure 2
Figure 2. Factors that determine macrophage phenotype(s) in atherosclerotic lesions
Macrophages in atherosclerotic lesions display markers characteristic of several in vitro-differentiated macrophage phenotypes, which suggest possible factors and receptors that determine their differentiation from monocytes and their function in vivo. The growth factor M-CSF is almost universally required for the monocyte to macrophage differentiation (except M4 macrophages), whereas GM-CSF appears to promote a highly pro-inflammatory phenotype. IFN-γ and LPS polarize macrophages into an M1 phenotype, whereas IL4 (and IL13) and a number of other factors discussed in this review lead to M2 polarization. CXCL4 acts through an unidentified chondroitin sulfate proteoglycan receptor, while IL-17 promotes proliferation of mouse macrophages in vitro and macrophage accumulation in vivo . CX3CL1 binding to its receptor CX3CR1 can promote macrophage survival. Macrophages in atherosclerotic lesions accumulate excessive amounts of lipid, and numerous intracellular lipid droplets make the neointimal macrophages look like “foam cells.” Regulated uptake of native LDL via the family of LDL receptors (LDLR, ApoER and LRP1) plays a limited role in foam cell formation. The major mechanism of excessive lipid accumulation is via unregulated uptake of oxidized (oxLDL), minimally modified (mmLDL), acetylated (acLDL) or otherwise modified LDL. This uptake is mediated by CD36 (alone or as heterodimer with TLR2), SRA, LOX-1, CXCL16, TLR4/MD-2 and a number of other receptors. Unmodified LDL also enters macrophages by micro- and macro-pinocytosis. The ABC transporters ABCA1, ABCG1 and ABCA4/7 mediate reverse transport (efflux) of cholesterol, oxysterols and phospholipids, but the presence of foam cells in the lesions indicates that the efflux mechanisms become eventually overwhelmed by unregulated LDL uptake. Lipid accumulation has profound effects on the macrophage gene expression, adhesion, apoptosis, efferocytosis and other characteristics and functions.
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