Modulating Oxysterol Sensing to Control Macrophage Apoptosis and Atherosclerosis
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Atherosclerosis is the silent underlying cause of acute myocardial infarction and stroke, some of the most common causes of mortality worldwide. Aside from managing risk factors, such as hyperlipidemia, few therapies can be said to directly target atherosclerotic plaque progression partially because of remaining gaps in basic knowledge of the disease. Atherosclerosis is initiated by endothelial injury and deposition of lipids in the subendothelial layer called the intima. Circulating monocytes traffic to the site of injury, transmigrate through the endothelium, and differentiate to macrophages in an attempt to repair damage and remove lipids, much of which include deleterious oxidatively modified forms. Subsequently, plaque macrophages become central players in the progression of atherosclerosis because of a feedforward cycle of rampant lipid accumulation, proinflammatory cytokine release, cell death, and further monocyte recruitment.
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A major area of focus in the field is in understanding why macrophages cannot efficiently clear lipid and cell debris deposits. Lipid species in the plaque, including oxidized low-density lipoprotein (oxLDL), are known to induce apoptotic cell death, though the precise lipid species and signal transduction mechanisms involved are unclear. This apoptotic response may actually be adaptive in the early stages of plaque development because secondary macrophages can adeptly clear apoptotic cells through efferocytosis before cell-intrinsic damage becomes overwhelming (Figure, top left). Indeed, many features of apoptotic cell death, including expression of eat-me surface signals, are purposed toward efferocytic clearance. In contrast, secondary necrosis occurs when apoptotic cells are left unengulfed, resulting in uncontrolled disintegration, release of cytosolic components, and damage to local tissue.1 Advanced plaques lack efficient efferocytosis such that many apoptotic cells progress to secondary necrosis, adding to plaque size and complexity (Figure, top right). Thus, understanding mechanisms of apoptotic cell death in atherosclerotic plaque macrophages and the impact on overall …