Macrophage death and defective inflammation resolution in atherosclerosis - PubMed (original) (raw)

Review

Macrophage death and defective inflammation resolution in atherosclerosis

Ira Tabas. Nat Rev Immunol. 2010 Jan.

Abstract

A key event in atherosclerosis is a maladaptive inflammatory response to subendothelial lipoproteins. A crucial aspect of this response is a failure to resolve inflammation, which normally involves the suppression of inflammatory cell influx, effective clearance of apoptotic cells and promotion of inflammatory cell egress. Defects in these processes promote the progression of atherosclerotic lesions into dangerous plaques, which can trigger atherothrombotic vascular disease, the leading cause of death in industrialized societies. In this Review I provide an overview of these concepts, with a focus on macrophage death and defective apoptotic cell clearance, and discuss new therapeutic strategies designed to boost inflammation resolution in atherosclerosis.

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Figures

Figure 1

Figure 1. Schematic of a dangerous, or “vulnerable,” atherosclerotic plaque showing the hallmarks of defective resolution of inflammation

Inflammatory cells, including lipid-laden macrophage (Mφ) foam cells, have accumulated in the intima, resulting from both persistent influx of new cells, particularly monocytes, and defective egress of the resident cells. Moreover, dead macrophages are not efficiently cleared by the process of efferocytosis, and so they undergo post- apoptotic necrosis. This process contributes to the formation of the necrotic core, which contributes to plaque disruption, particularly thinning of the fibrous cap. If the process continues, there will be a breach in the fibrous cap, leading to lumenal thrombosis and arterial occlusion.

Figure 2

Figure 2. Efferocytosis and inflammation resolution in early and advanced atherosclerosis

A In early atherosclerotic lesions, efferocytosis is efficient, leading to rapid clearing of apoptotic macrophages (Mφs). This process prevents post-apoptotic cellular necrosis, elicits the production of anti-inflammatory cytokines, and clears macrophages from the lesions. The result of this inflammation resolution process is decreased plaque progression. B In advanced lesions, efferocytes do not function properly and this apoptotic macrophages become secondarily necrotic. The necrotic material is a stimulus for inflammation, and the normal anti-inflammatory signaling associated with efferocytosis does not occur. Moreover, an important mean for ridding the lesion of inflammatory macrophages is lost. Thus, inflammation resolution fails to occur normally, and necrotic macrophages coalesce into necrotic cores. These features define plaques that are vulnerable to rupture. which in turn can trigger acute lumenal thrombosis and arterial occlusion.

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