The rapid and efficient removal of apoptotic cells is an important feature of embryonic development, tissue maintenance and wound healing, as well as immune responses. If apoptotic cells are not removed promptly, there is a risk of secondary necrosis and inflammation. But how do phagocytes know where to find dying cells? A study in Cell now shows that apoptotic cells, as well as presenting 'eat me' signals on the cell surface, release a chemoattractant that guides phagocytic cells to the site of cell death.

To test the theory that dying apoptotic cells might release attractant signals for phagocytes, Lauber and colleagues assessed the supernatants from cells that had been induced to undergo apoptosis by ultraviolet radiation or pharmacological inducers such as staurosporine. Supernatants from dying cells induced the migration of various monocytic-cell lines in transmigration assays. Supernatant from apoptotic MCF7 breast tumour cells — which are deficient for the pro-apoptotic molecule caspase-3 — induced minimal migration compared with other cell lines. But supernatant from MCF7 cells that stably express caspase-3 did induce migration, and this could be inhibited by treatment with the caspase inhibitor zVAD-fmk, indicating that the process was caspase-3 dependent.

Next, the authors investigated the nature of the chemoattractant signal in the supernatants. Treatment with proteinase K, DNase or RNase had no effect, so the chemoattractant could not be protein, DNA or RNA. The factor could be extracted with chloroform or diethyl ether, indicating that it was a lipid. The authors then tested a series of active phospholipids and found that lysophosphatidylcholine (LPC) and platelet-activating factor (PAF) could neutralize the chemotactic effect when added to the responding cells in transmigration assays, but only LPC could directly induce the migration of monocytes. Injection of supernatants from apoptotic cells into the peritoneum resulted in a greater macrophage infiltration than did administration of supernatant from non-apoptotic cells.

How is LPC generated in dying cells? Further experiments showed that LPC is generated as a result of caspase-3-mediated activation of the calcium-independent phospholipase A2.This work shows that apoptotic cells attract professional phagocytes by releasing recruitment signals to ensure that dying cells are promptly dealt with and so prevent secondary necrosis.