The walking dead: macrophage inflammation and death in atherosclerosis

Abstract

Purpose of review: To highlight recent studies that describe novel inflammatory and signaling mechanisms that regulate macrophage death in atherosclerosis.

Recent findings: Macrophages contribute to all stages of atherosclerosis. The traditional dogma states that in homeostatic conditions, macrophages undergo apoptosis and are efficiently phagocytosed to be cleared by a process called efferocytosis. In advanced atherosclerosis, however, defective efferocytosis results in secondary necrosis of these uncleared apoptotic cells, which ultimately contributes to the formation of the characteristic necrotic core and the vulnerable plaque. Here, we outline the different types of lesional macrophage death: apoptosis, autophagic and the newly defined necroptosis (i.e. a type of programmed necrosis). Recent discoveries demonstrate that macrophage necroptosis directly contributes to necrotic core formation and plaque instability. Further, promoting the resolution of inflammation using preresolving mediators has been shown to enhance efferocytosis and decrease plaque vulnerability. Finally, the canonical 'don't eat me' signal CD47 has recently been described as playing an important role in atherosclerotic lesion progression by impairing efficient efferocytosis. Although we have made significant strides in improving our understanding of cell death and clearance mechanisms in atherosclerosis, there still remains unanswered questions as to how these pathways can be harnessed using therapeutics to promote lesion regression and disease stability.

Summary: Improving our understanding of the mechanisms that regulate macrophage death in atherosclerosis, in particular apoptosis, necroptosis and efferocytosis, will provide novel therapeutic opportunities to resolve atherosclerosis and promote plaque stability.

Figure 1. Macrophage Apoptosis, Autophagy and Necroptosis in Atherosclerosis

In early lesions, modified lipoproteins (e.g. oxLDL) act as inflammatory stimuli within the vessel wall to recruit circulating monocytes, which avidly phagocytose these modified lipids to become macrophage foam cells. These cells then eventually undergo 3 main types of cell death within the vessel wall: apoptosis, autophagy-related cell death and necroptosis. Macrophages that undergo apoptosis can be efficiently efferocytosed to be cleared by other macrophages (purple), whereas necroptotic macrophages are ineffectively efferocytosed (grey), resulting in the accumulation of inflammatory stimuli within the intima that propagates atherosclerosis. Together, both increased cell death and defective efferocytosis ultimately results in the formation of the necrotic core, which is the hallmark of a rupture-prone, vulnerable plaque.