Leukocyte migratory responses to apoptosis: the attraction and the distraction

An expanding body of evidence demonstrates that cells undergoing apoptosis send out a selection of molecular navigational signals including proteins, lipids and nucleotides that serve to recruit phagocytes to the dying targets which are subsequently engulfed and removed. This homeostatic process is essentially non-phlogistic, contrasting markedly with the acute inflammatory responses elicited in phagocytes by damaging or infectious agents. The "professional" scavengers of apoptotic cells are mononuclear phagocytes-the macrophages-and sites of high-rate apoptosis are clearly characterized by macrophages associated with the apoptotic cells. By contrast, members of the other class of professional phagocytes-the granulocytes-are not recruited to sites of apoptosis as a direct consequence of the cell-death program. Indeed, recent work indicates that apoptotic cells release a mixture of migratory cues to leukocytes in order to selectively attract mononuclear phagocytes but not granulocytes through functional balancing of positive and negative signals. Here we discuss these molecular mechanisms which not only serve as migratory cues but also may activate responding phagocytes to engulf apoptotic cells effectively. Finally, we speculate upon new therapeutic opportunities these mechanisms offer for a range of pathological conditions, including inflammatory disorders and cancer.