Mechanisms and consequences of macrophage apoptosis in atherosclerosis

Abstract

Macrophage apoptosis is an important feature of atherosclerotic plaque development. Research directed at understanding the functional consequences of macrophage death in atherosclerosis has revealed opposing roles for apoptosis in atherosclerotic plaque progression. In early lesions, macrophage apoptosis limits lesion cellularity and suppresses plaque progression. In advanced lesions, macrophages apoptosis promotes the development of the necrotic core, a key factor in rendering plaques vulnerable to disruption and in acute lumenal thrombosis. The first section of this review will examine the role of phagocytic clearance of apoptotic macrophages, a process known as efferocytosis, in the dichotomous roles of macrophage apoptosis in early vs. advanced lesions. The second section will focus on the molecular and cellular mechanisms that are thought to govern macrophage death during atherosclerosis. Of particular interest is the complex and coordinated role that the endoplasmic reticulum (ER) stress pathway and pattern recognition receptors (PRRs) may play in triggering macrophage apoptosis.

Fig. 1.

Model of the functional consequences of macrophage apoptosis in early and advanced lesions. In early lesions, monocytes surveying the vascular wall are recruited to the developing plaque. The monocytes differentiate into macrophages in areas where modified and remnant lipoproteins are retained in the extracellular matrix. Macrophages become foam cells by ingesting lipoproteins and storing these lipids in droplets. The engorged foam cells secrete a variety of proinflammatory cytokines and then eventually undergo apoptosis. Rapid efferocytic clearance of the apoptotic cells leads to suppression of the proinflammatory response. The overall effect is a reduction in lesion cellularity and size. In advanced lesions, the apoptotic macrophages are not efficiently cleared by efferocytosis. The apoptotic macrophages that accumulate eventually undergo secondary necrosis. The buildup of necrotic debris promotes inflammation, plaque instability, and acute thrombosis.

Fig. 2.

Potential inducers of macrophage apoptosis in atherosclerotic lesions. Macrophage apoptosis can be triggered by a variety of factors that work alone or, most likely, in combination to trigger macrophage death. The buildup of endogenous ligands that are recognized by SRA, CD36, and toll-like receptors (TLRs) trigger a proinflammatory and apoptotic response during ER stress. See text for details. AGE, advanced glycation end-products; MMP, matrix metalloproteinase; PRR, pattern recognition receptors; TNF-α, tumor necrosis factor-α.