Like a well-trained police dog, a macrophage responds to a signal that means “let go.” Tsai and Discher reveal that the signal works by blocking a molecular motor that helps drag bacteria and other potential enemies into the macrophage.
Macrophages sweep up pathogens while leaving our own cells alone. A two-step procedure for recognizing intruders helps avoid misdirected attacks. In the first step, macrophages snare and begin swallowing objects studded with IgG antibodies, which usually latch onto interlopers. But the antibodies are sloppy, sometimes attaching to the body's own cells. So before a macrophage engulfs its target, it also checks for a second form of identification, the protein CD47. If a “self” version of CD47 is present, it induces the macrophage to disengage. How CD47 spurs a macrophage to stop mid-swallow was uncertain.
To find out, Tsai and Discher followed human macrophages as they tangled with human and sheep red blood cells. When a macrophage meets its quarry, actin molecules flock to the contact site and polymerize, extending the cell's membrane around the target. Another protein called nonmuscle myosin also moves in. It contracts to help reel in the partly engulfed object. The researchers found that actin and nonmuscle myosin relocated normally when the macrophages encountered sheep red blood cells, which sport a “foreign” version of CD47. But when the targets were human red blood cells—which carry self CD47—only actin is mobilized.
Further experiments indicated that CD47 exerts its effects through its receptor on macrophages, SIRPα, which in turn indirectly inactivates the myosin by preventing the addition of a phosphate group to the brawny molecule. By shutting down a pulling protein needed to complete phagocytosis, the researchers conclude, self CD47 prevents cells that carry it from being eaten. The team speculates that macrophages benefit from the two-step recognition process because it allows them to restrain a potential troublemaker while checking its credentials. As a result, they are poised to gobble the target if it turns out to be a threat.