Atherosclerotic lesions in mice and humans switch on a ‘don’t eat me’ signal—expression of CD47—that prevents effective removal of diseased tissue; anti-CD47 antibody therapy can normalize this defective efferocytosis, with beneficial results in several mouse models of atherosclerosis. Nicholas Leeper and colleagues demonstrate that atherosclerotic lesions in mice and humans switch on a 'don't eat me' signal — in the form of expression of the anti-phagocytic transmembrane protein CD47 — that prevents effective removal of diseased tissue. They show that administration of anti-CD47 antibodies can normalize this defective phagocytic clearance (or ‘efferocytosis’) with beneficial results in several mouse models of atherosclerosis. These results suggest that targeted pro-efferocytic therapies could have potential in cardiovascular diseases. Atherosclerosis is the disease process that underlies heart attack and stroke1. Advanced lesions at risk of rupture are characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris2. Why these cells are not cleared remains unknown3. Here we show that atherogenesis is associated with upregulation of CD47, a key anti-phagocytic molecule that is known to render malignant cells resistant to programmed cell removal, or ‘efferocytosis’4,5,6,7. We find that administration of CD47-blocking antibodies reverses this defect in efferocytosis, normalizes the clearance of diseased vascular tissue, and ameliorates atherosclerosis in multiple mouse models. Mechanistic studies implicate the pro-atherosclerotic factor TNF-α as a fundamental driver of impaired programmed cell removal, explaining why this process is compromised in vascular disease. Similar to recent observations in cancer5, impaired efferocytosis appears to play a pathogenic role in cardiovascular disease, but is not a fixed defect and may represent a novel therapeutic target.

The necrotic core has long been a hallmark of the vulnerable atherosclerotic plaque. Although apoptotic cells are cleared quickly in almost all other tissue beds, their removal appears to be significantly impaired in the diseased blood vessel. Emerging evidence indicates that this phenomenon is caused by a defect in efferocytosis, the process by which apoptotic tissue is recognized for engulfment by phagocytic cells such as macrophages. Genetic and experimental data suggest that efferocytosis is impaired during atherogenesis caused by dysregulation of so-called eat me ligands, which govern the edibility of cells undergoing programmed cell death. The following is a summary of recent data indicating that efferocytosis is a major unappreciated driver of lesion expansion but also a reversible defect that can potentially be targeted as a means to prevent plaque progression.