Monocyte Recruitment, Specification, and Function in Atherosclerosis

Abstract

Atherosclerotic lesions progress through the continued recruitment of circulating blood monocytes that differentiate into macrophages within plaque. Lesion-associated macrophages are the primary immune cells present in plaque, where they take up cholesterol and store lipids in the form of small droplets resulting in a unique morphology termed foam cell. Recent scientific advances have used single-cell gene expression profiling, live-cell imaging, and fate mapping approaches to describe macrophage and monocyte contributions to pro- or anti-inflammatory mechanisms, in addition to functions of motility and proliferation within lesions. Yet, many questions regarding tissue-specific regulation of monocyte-to-macrophage differentiation and the contribution of recruited monocytes at stages of atherosclerotic disease progression remain unknown. In this review, we highlight recent advances regarding the role of monocyte and macrophage dynamics in atherosclerotic disease and identify gaps in knowledge that we hope will allow for advancing therapeutic treatment or prevention strategies for cardiovascular disease.

Keywords: atherosclerosis; cardiovascular disease; inflammation; macrophage; monocyte; trafficking.

Figure 1

Developmental heterogeneity of monocyte populations. (A) Classical model (green arrow) of monocyte development shows monocytes are generated through Macrophage (Mφ) and DC Precursors (MDPs). Emerging evidence (red, blue arrows) suggest monocytes can be generated through the Granulocyte and Macrophage Progenitors (GMPs). Ly6C^hi monocytes give rise to Ly6C^lo monocytes in (B) blood or monocyte-derived macrophages in (C) peripheral tissues.

Figure 2

Monocyte and macrophage dynamics in the aorta. (A) Adventitia macrophages (Mφ) that develop during embryonic development and immediately following birth are complemented by a wave of monocytes. In the intima, aorta-intima-resident macrophages (Mac^AIR) develop from bone marrow monocytes immediately following birth. (B) During homeostasis, adventitia and Mac^AIR are maintained in their respective tissues, independent of additional monocyte supplementation, through local proliferation. (C) During atherosclerosis, the role of adventitia macrophages is poorly described and their relationship with plaque-associated macrophages is unknown. During disease progression, Mac^AIR are the initial cells to differentiate into foamy macrophages. Subsequently, monocytes infiltrate into tissue and differentiate into inflammatory or foamy macrophages. The interactions between these monocyte-derived cell types and their potential contributions to cell death pathways are unclear.