Macrophages, Atherosclerosis and the Potential of netrin-1 As a Novel Target for Future Therapeutic Intervention

Abstract

Atherosclerosis is a chronic inflammatory disease that is distinguished by the persistence of cholesterol-laden macrophages in plaques of the arterial wall[1]. Based on observational studies that extend into the era of modern atherosclerosis research (which dates to the introduction in the early 90's of mouse models of the disease), the prevailing view has been that the recruitment of monocytes into atherosclerotic plaques is an unproductive exercise, in which these cells are fated to become macrophage foam cells that persist in this site, establishing chronic inflammation, until eventually dying by either necrosis or apoptosis. Unlike in other tissues, macrophages that accumulate in plaques appear to have a diminished capacity to migrate[2–5], and go from being chemotactic to chemostatic, thereby contributing to a failure to resolve the inflammatory process in arteries set in motion by the retention of atherogenic lipoproteins. Moreover, the impaired efferocytotic ability of these macrophages prevents the clearance of their dying compatriots[6], further contributing to the pro-inflammatory milieu of the plaque and ultimately resulting in the formation of a necrotic core. In such unstable plaques, inflammasome-activating cholesterol crystals[7] and pro-thrombotic tissue factor accumulate in this graveyard of dead macrophages, further adding to the mayhem.