Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance.
Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance.
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凋亡细胞的吞噬去除在体内有效地发生，使得即使在具有显著凋亡的组织中，也检测到非常少的凋亡细胞。这被认为是由于凋亡细胞释放find-me信号，其募集运动吞噬细胞如单核细胞、巨噬细胞和树突细胞，导致死亡细胞的迅速清除。然而，这种发现我的信号的身份和体内相关性还没有很好地理解。在这里，通过几条证据线，我们确定细胞外核苷酸作为一个关键的凋亡细胞发现我的信号。我们证明了原代胸腺细胞和细胞系在凋亡的早期阶段ATP和UTP（等摩尔量）的caspase依赖性释放。这些浓度的纯化核苷酸足以诱导与凋亡细胞上清液相当的单核细胞募集。酶促去除ATP和UTP（通过腺苷三磷酸双磷酸酶或异位CD 39表达）废除了凋亡细胞上清液在体外和体内招募单核细胞的能力。然后，我们确定了ATP/UTP受体P2 Y2作为一个关键的传感器的核苷酸释放的凋亡细胞使用RNAi消耗研究单核细胞，巨噬细胞从P2 Y2-null小鼠。通过两种方法揭示了核苷酸在凋亡细胞清除中的体内相关性。首先，在小鼠气囊模型中，凋亡细胞上清液诱导的单核细胞和巨噬细胞的募集是健康细胞上清液的三倍;这种募集被核苷酸耗尽所消除，并在P2 Y2 −/−小鼠中显著减少。第二，清除凋亡的胸腺细胞显着受损，无论是耗尽的核苷酸或干扰P2 Y受体功能（通过药理学抑制，或在P2 Y2 −/−小鼠）。这些结果确定核苷酸作为一个关键的发现我的线索释放的凋亡细胞，以促进P2 Y2依赖的吞噬细胞的招聘，并提供了强有力的证据，发现我的信号和体内有效的尸体清除之间的明确关系。
Phagocytic removal of apoptotic cells occurs efficiently in vivo such that even in tissues with significant apoptosis, very few apoptotic cells are detectable. 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 cells. 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 apoptotic cell supernatants. Enzymatic removal of ATP and UTP (by apyrase or ectopic CD39 expression) 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 RNAi depletion studies in monocytes, and macrophages from P2Y2-null mice. The in vivo relevance of nucleotides in apoptotic cell clearance was revealed by two approaches. First, in a murine air-pouch model, apoptotic cell supernatants induced a three-fold greater recruitment of monocytes and macrophages compared to supernatants from healthy cells; this recruitment was abolished by depletion of nucleotides and significantly decreased in P2Y2−/− 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 phagocyte recruitment, and provide strong evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo.
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