来自北卡罗来那大学医学院的研究人员发现凋亡细胞释放ATP和UTP，它们对表达P2Y2 ATP/UTP受体的吞噬细胞来说充当一种“找到我”信号及化学引诱剂。
细胞凋亡几乎在所有组织中都出现，是正常发育和体内平衡的构成部分。不过，即使在有较高细胞周转率的组织中，凋亡细胞也很少见；这种现象一直被归因于凋亡细胞具有这样一种能力：它们能够通过“找到我”信号的释放来表示自己的存在，从而招来吞噬细胞，立即启动清除过程。然而，凋亡细胞所释放的是哪种类型的“找到我”信号以及这些信号是怎样被吞噬细胞检测到的仍不清楚。在这篇论文中，研究人员发现凋亡细胞释放ATP和UTP，它们对表达P2Y2 ATP/UTP受体的吞噬细胞来说充当一种“找到我”信号及化学引诱剂。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature 461, 282-286 (10 September 2009) | doi:10.1038/nature08296
Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance
Michael R. Elliott1,2, Faraaz B. Chekeni1,3, Paul C. Trampont1,2, Eduardo R. Lazarowski7, Alexandra Kadl4, Scott F. Walk1,2, Daeho Park1,2, Robin I. Woodson5, Marina Ostankovich4, Poonam Sharma4, Jeffrey J. Lysiak5, T. Kendall Harden8, Norbert Leitinger3,4 & Kodi S. Ravichandran1,2,6
1 Beirne B. Carter Center for Immunology Research,
2 Center for Cell Clearance,
3 Department of Pharmacology,
4 Robert M. Berne Cardiovascular Research Center,
5 Department of Urology,
6 Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA
7 Department of Medicine,
8 Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Phagocytic removal of apoptotic cells occurs efficiently in vivo such that even in tissues with significant apoptosis, very few apoptotic cells are detectable1. This is thought to be due to the release of 'find-me' signals by apoptotic cells that recruit motile phagocytes such as monocytes, macrophages and dendritic cells, leading to the prompt clearance of the dying cells2. However, the identity and in vivo relevance of such find-me signals are not well understood. Here, through several lines of evidence, we identify extracellular nucleotides as a critical apoptotic cell find-me signal. We demonstrate the caspase-dependent release of ATP and UTP (in equimolar quantities) during the early stages of apoptosis by primary thymocytes and cell lines. Purified nucleotides at these concentrations were sufficient to induce monocyte recruitment comparable to that of apoptotic cell supernatants. Enzymatic removal of ATP and UTP (by apyrase or the expression of ectopic CD39) abrogated the ability of apoptotic cell supernatants to recruit monocytes in vitro and in vivo. We then identified the ATP/UTP receptor P2Y2 as a critical sensor of nucleotides released by apoptotic cells using RNA interference-mediated depletion studies in monocytes, and macrophages from P2Y2-null mice3. The relevance of nucleotides in apoptotic cell clearance in vivo was revealed by two approaches. First, in a murine air-pouch model, apoptotic cell supernatants induced a threefold greater recruitment of monocytes and macrophages than supernatants from healthy cells did; this recruitment was abolished by depletion of nucleotides and was significantly decreased in P2Y2 -/- (also known as P2ry2 -/-) mice. Second, clearance of apoptotic thymocytes was significantly impaired by either depletion of nucleotides or interference with P2Y receptor function (by pharmacological inhibition or in P2Y2 -/- mice). These results identify nucleotides as a critical find-me cue released by apoptotic cells to promote P2Y2-dependent recruitment of phagocytes, and provide evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo.
