Many receptors can tether (left), but few can engulf (right)

When it comes to receptors for the phagocytosis of apoptotic cells, many have been proposed, but none has been proven. Now, Hoffmann et al. (page 649) report that a receptor for phosphatidylserine (PS) is uniquely required for engulfment of apoptotic cells, whereas a large number of other proposed receptors may function only in attachment of the apoptotic cell to the phagocytic cell. PS is exposed on the outer leaflet of cells when they become apoptotic, and thus it acts as a specific identifier of apoptotic cells. As for attachment to the phagocyte, it seems that pretty much anything will do.

Hoffmann et al. use a clever trick to get around the complexity of the surface of an apoptotic cell. Instead of apoptotic cells they use a novel target: red blood cells coated with a sandwich of biotin, avidin, and a single biotinylated protein. This allows them to test the function of a single protein in phagocyte recognition, rather than having to interpret the results of blocking experiments, which are complicated by redundancy and an inability to tell which step is being blocked.

Attachment is mediated by targets of any one of the many proposed receptors. But only added PS results in engulfment. The PS stimulates macropinocytosis, a process in which the cell takes large gulps from its surroundings by forming membrane ruffles that fold over and fuse to each other. In contrast, classic, receptor-mediated endocytosis involves the extension of a single pseudopod via sequential receptor engagement.Macropinocytosis can also be stimulated by several growth factors, and this stimulation plus attachment is also sufficient for phagocytosis. This promiscuous phagocytic behavior is consistent with the finding that many, if not all, cells can act as phagocytes. Hoffmann et al. suggest that one of the things that distinguish classic phagocytes, such as macrophages, is the plethora of receptor molecules that are available on their surface for the initial tethering stage. ▪