Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment

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Abstract
Macrophage recognition and ingestion of ‘self’ cells undergoing apoptosis in vivo protects tissues from the toxic contents of dying cells and modulates macrophage regulation of inflammatory and immune responses1,2. However, the complex molecular mechanisms mediating macrophage discrimination between viable and apoptotic cells are poorly understood2,3. In particular, little is known of why viable nucleated cells are not engulfed by macrophages. To reveal active repulsion of viable cells and to seek specific capture or ‘tethering’ of apoptotic cells, we studied macrophage binding of viable and apoptotic leukocytes under conditions of flow. We found that homophilic ligation of CD31 (ref. 4) on viable leukocytes promoted their active, temperature-dependent detachment under low shear, whereas such CD31-mediated detachment was disabled in apoptotic leukocytes, promoting tight binding and macrophage ingestion of dying cells. Here we propose that CD31 (also known as platelet-endothelial cell adhesion molecule-1, PECAM-1) is an example of a cell-surface molecule that prevents phagocyte ingestion of closely apposed viable cells by transmitting ‘detachment’ signals, and which changes function on apoptosis, promoting tethering of dying cells to phagocytes.