The paucity of detectable apoptotic cells in tissues where many cells undergo apoptosis demonstrates the efficiency of cell-clearance mechanisms. Apoptotic cells are thought to release factors that signal their presence to scavenger cells such as macrophages, but the nature of these signals is unclear (see commentary by Gregory). Elliott et al. found that supernatant from thymocytes in which apoptosis was induced recruited more monocytes in a migration assay than did supernatant from live cells. Similarly, supernatant from apoptotic cells introduced into a subcutaneous air pouch in mice recruited more macrophages than did supernatant from live cells. Treatment of the supernatant from the apoptotic cells with apyrase, which hydrolyzes nucleoside triphosphates and diphosphates, blocked the recruitment of macrophages to the air pouch. Of various nucleotides tested, ATP and UTP were the most efficient at recruiting monocytes in in vitro migration assays, and both nucleotides were detectable in the supernatants of cells within 2 hours of the induction of apoptosis. Treatment of cells with a caspase inhibitor before triggering apoptosis blocked the release of ATP and UTP into the culture medium. Supernatant from apoptotic cells administered to air pouches in mice deficient in P2Y2, a G protein–coupled receptor for ATP and UTP, recruited fewer macrophages than were recruited when comparable experiments were performed with wild-type (WT) mice. In addition, treatment of P2Y2-deficient mice with dexamethasone, which triggers the apoptosis and clearance of thymocytes, resulted in the presence of far more apoptotic thymocytes in the thymus than occurred in WT mice. Together, these data suggest that ATP and UTP are factors released by apoptotic thymocytes that trigger the recruitment of the macrophages needed to clear them from the tissue.
M. R. Elliott, F. B. Chekeni, P. C. Trampont, E. R. Lazarowski, A. Kadl, S. F. Walk, D. Park, R. I. Woodson, M. Ostankovich, P. Sharma, J. J. Lysiak, T. K. Harden, N. Leitinger, K. S. Ravichandran, Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286 (2009). [PubMed]
C. Gregory, Sent by the scent of death. Nature 461, 181–182 (2009). [PubMed]