Nucleotides released by apoptotic cells act as a find-me signal for phagocytic clearance

By Michael R. Elliott, Faraaz B. Chekeni, P. Trampont, E. Lazarowski, A. Kadl, S. Walk, Daeho Park, Robin I. Woodson, Marina Ostankovich, Poonam Sharma and 4 more. Nature, 2009

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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 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 mice. 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.

Subfields: Immunology, Obstetrics and Gynecology, Physiology

View Paper: https://www.semanticscholar.org/paper/3e3560354b246546429247e0dbc071b529c4f651

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Citations in the corpus

Programmed Cell Death in Animal Development and Disease (2011, positive): “In addition, ATP and UTP nucleotides, released by the PANX1 channel, have been suggested to act as ‘‘find me’’ signals (Elliott et al., 2009).”
Senescent cells as a source of inflammatory factors for tumor progression (2010, result): “Similar to recent data showing that apoptotic cells release “find-me signals”, which recruit innate immune to clear the dying cells, senescent cells also secrete HMGB1, known to recruit and activate cells from the innate immune system [96].”
Decoding cell death signals in liver inflammation. (2013, background): “ATP UTP Purine metabolites NLRP3 inflammasome activators P2RX7 P2Y2 Secreted via autophagyand PANX1-dependent mechanisms Involved in the pathogenesis of conA-induced acute liver injury [127, 128, 143]”
A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death (2012, positive): “…been mostly associated with mechanical/osmotic strain (Nandigama et al , 2006), cells in early apoptotic stages, during which caspases are active (Elliott et al , 2009; Chekeni et al , 2010) or in mid apoptotic stages, coincident with nuclear fragmentation (Ghiringhelli et al , 2009; Martins et…”
Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. (2013, background): “P2RY2-conveyed signals are required for the recruitment, persistence, and differentiation of DC precursors and neutrophils into the tumor bed (Elliott et al., 2009; Ma et al., 2013).”