Heterogeneous in vivo behavior of monocyte subsets in atherosclerosis

Abstract

Monocytes and macrophages play active roles in atherosclerosis, a chronic inflammatory disease that is a leading cause of death in the developed world. The prevailing paradigm states that, during human atherogenesis, monocytes accumulate in the arterial intima and differentiate into macrophages, which then ingest oxidized lipoproteins, secrete a diverse array of proinflammatory mediators, and eventually become foam cells, the key constituents of a vulnerable plaque. Yet monocytes are heterogeneous. In the mouse, one subset (Ly-6C(hi)) promotes inflammation, expands in hypercholesterolemic conditions, and selectively gives rise to macrophages in atheromata. A different subset (Ly-6C(lo)) attenuates inflammation and promotes angiogenesis and granulation tissue formation in models of tissue injury, but its role in atherosclerosis is largely unknown. In the human, monocyte heterogeneity is preserved but it is still unresolved how subsets correspond functionally. The contradistinctive properties of these cells suggest commitment for specific function before infiltrating tissue. Such commitment argues for discriminate targeting of deleterious subsets while sparing host defense and repair mechanisms. In addition to advancing our understanding of atherosclerosis, the ability to target and image monocyte subsets would allow us to evaluate drugs designed to selectively inhibit monocyte subset recruitment or function, and to stratify patients at risk for developing complications such as myocardial infarction or stroke. In this review we summarize recent advances of our understanding of the behavioral heterogeneity of monocytes during disease progression and outline emerging molecular imaging approaches to address key questions in the field.

Figure 1. Molecular Imaging modalities that inform on monocyte/macrophage presence and function

Monocyte/macrophages and associated functions have been imaged with different molecular imaging modalities at different sensitivities and resolutions. Imaging of macrophages or function has been achieved with PET/CT (image shows uptake of ⁶⁴Cu targeted nanoparticles by macrophages); SPECT/CT (image shows accumulation of exogenously-labeled and adoptively injected ¹¹¹In-monocytes); MRI (image shows accumulation of macrophage-targeted immunomicelles); CT (image shows uptake of CT-contrast agent N1177 by macrophages); FMT (image shows uptake of fluorescent nanoagents by macrophages; unpublished); and FRI (image shows protease-activatable regions of an excised rabbit aorta). To gain insight into the differential in vivo behavior of monocyte subsets, promising tools involve IVM (top image shows patrolling Ly-6C^lo monocytes; bottom image shows Ly-6C^hi-associated proteolysis88) and the development of novel monocyte subset-targeted agents (image shows specificity of an agent for activated but not resting macrophages).

Figure 2. Model for the role of monocyte subtypes in experimental mouse atherosclerosis

Elevated levels of cholesterol or lipid derivatives (‘Lipids’) expand the Ly-6C^hi monocyte repertoire in circulation by several mechanisms that include reduction of cell apoptosis, increased proliferation and impaired Ly-6C^hi → Ly-6C^lo conversion. Ly-6C^hi monocytes are recruited to atherosclerotic lesions via the CCR2, CCR5 and CX₃CR1 chemokine receptors. The recruited cells differentiate massively into macrophages, although some cells can acquire a DC phenotype. Lesional macrophages eventually become foam cells and participate in plaque development, rupture and thrombosis. Ly-6C^lo monocytes do no expand in periphery and infiltrate lesions less frequently than Ly-6C^hi monocytes. Their recruitment depends on CCR2, but may not require CX₃CR1. Ly-6C^lo cells exhibit phagocytic and pro-angiogenic functions, and may preferentially mature into DC in lesions, however their participation in disease progression remains largely unknown.