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.
Highlights
CONSEQUENCES OF MACROPHAGE DEATHMacrophages play crucial roles as a primary line of defense against infectious pathogens and foreign material and by ridding tissues of apoptotic debris
Macrophage apoptosis is an important feature of atherosclerotic plaque development
We summarize the evidence supporting this dichotomous model of lesional macrophage death and discuss new concepts related to mechanisms of macrophage apoptosis and phagocytic clearance of apoptotic cells
Summary
Macrophages play crucial roles as a primary line of defense against infectious pathogens and foreign material and by ridding tissues of apoptotic debris. Another study demonstrated reduced macrophage apoptosis and increased lesion size in Ldlr2/2 mice reconstituted with Bax-deficient bone marrow [12]. The beneficial aspect of early lesional macrophage death has been documented using mice deficient in the prosurvival molecule AIM (apoptosis inhibitor expressed by macrophages; called Spa or Api). This study found that Aim2/2;Ldlr2/2 macrophages were more susceptible to oxLDL-induced apoptosis, and double knockout mice exhibited accelerated macrophage death and a significant reduction in early lesion area [13]. Taken together, these findings support the concept that macrophage apoptosis in early lesions is beneficial by suppressing lesion cellularity
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