Clinical significance of macrophage phenotypes in cardiovascular disease

Abstract

The emerging understanding of macrophage subsets and their functions in the atherosclerotic plaque has led to the consensus that M1 macrophages are pro-atherogenic while M2 macrophages may promote plaque stability, primarily though their tissue repair and anti-inflammatory properties. As such, modulating macrophage function to promote plaque stability is an exciting therapeutic prospect. This review will outline the involvement of the different macrophage subsets throughout atherosclerosis progression and in models of regression. It is evident that much of our understanding of macrophage function comes from in vitro or small animal models and, while such knowledge is valuable, we have much to learn about the roles of the macrophage subsets in the clinical setting in order to identify the key pathways to target to possibly promote plaque stability.

Keywords: Atherosclerosis; Cardiovascular disease; M1; M2; Macrophage; Plaque stability; Review.

Figure 1

Proposed role of macrophage subsets in formation of the necrotic core. Monocytes are recruited early in atherosclerotic plaque development where, through the action of MCSF (and possibly IL-4, as evident in the mouse model), they differentiate into macrophages (Mϕ), primarily skewed towards an M2 form. Through the uptake of modified lipid they become foam cells. Apoptosis of the foam cells is accompanied by efferocytosis, primarily by M2 macrophages. As the plaque adopts an increasingly inflammatory environment, macrophage differentiation skews towards the M1 form and consequently, M1 foam cells predominate. As M1 macrophages have low efferocytosis capability, and there is a decreasing number of M2 efferocytes, apoptotic foam cells (including any remaining M2: dashed line in figure) undergo secondary necrosis promoting development of the necrotic core.

Figure 2

Macrophages in atherosclerotic plaque development. A-C representative heterogeneous foam cells from carotid atherosclerotic plaques. A: CD86 (brown), B: CD163 (brown) ADRP (green), C: CD206 (brown). D and E: macrophage collagen I expression. D: CD163 (green), procollagen I (red), nuclei (blue), CD163 and procollagen I co-expression (yellow). Inset: closer magnification of the cell in D indicated by white arrow head. E: CD86 (green: examples indicated by white arrow heads), procollagen I (red), nuclei (blue). Note, no CD86/procollagen I co-expression is evident as seen by absence of yellow. F: Proposed role of macrophage involvement in plaque progression. Lipoprotein enters the vessel wall where it is retained, in part, by binding to proteoglycans. Monocytes are recruited into the atherosclerotic plaque where they differentiate into different macrophage phenotypes (predominantly M2 in the early plaque) and uptake modified lipid adopting heterogenous foam cell forms (see also A-C). Apoptosis of the macrophages, in particular M2, is accompanied by efferocytosis, also primarily by M2 macrophages. As the plaque adopts an increasingly inflammatory environment, M1 foam cells predominate and defective efferocytosis increases, with subsequent necrosis leading to the formation of the necrotic core. In the advanced plaque, intraplaque haemorrhage promotes the formation of Mhem macrophages, which are athero-protective, partly due to reduced lipid accumulation and the production of collagen I. In contrast, M1 macrophages accumulate in the shoulder of the plaque contributing to thinning of the cap through MMP production. The destabilisation of the plaque leads to rupture of the plaque and thrombus formation. IPH = intraplaque haemorrhage, MV = microvessels, Mϕ = macrophage, PG = proteoglycan.