Microglia, brain immune cells, engage in the clearance of dead cells or dangerous debris, which is crucial to the maintenance of brain functions. When a neighbouring cell is injured, microglia move rapidly towards it or extend a process to engulf the injured cell. Because cells release or leak ATP when they are stimulated1,2 or injured3,4, extracellular nucleotides are thought to be involved in these events. In fact, ATP triggers a dynamic change in the motility of microglia in vitro5,6 and in vivo3,4, a previously unrecognized mechanism underlying microglial chemotaxis5,6; in contrast, microglial phagocytosis has received only limited attention. Here we show that microglia express the metabotropic P2Y6 receptor whose activation by endogenous agonist UDP triggers microglial phagocytosis. UDP facilitated the uptake of microspheres in a P2Y6-receptor-dependent manner, which was mimicked by the leakage of endogenous UDP when hippocampal neurons were damaged by kainic acid in vivo and in vitro. In addition, systemic administration of kainic acid in rats resulted in neuronal cell death in the hippocampal CA1 and CA3 regions, where increases in messenger RNA encoding P2Y6 receptors that colocalized with activated microglia were observed. Thus, the P2Y6 receptor is upregulated when neurons are damaged, and could function as a sensor for phagocytosis by sensing diffusible UDP signals, which is a previously unknown pathophysiological function of P2 receptors in microglia.
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Guthrie, P. B. et al. ATP released from astrocytes mediates glial calcium waves. J. Neurosci. 19, 520–528 (1999)
Koizumi, S., Fujishita, K., Tsuda, M., Shigemoto-Mogami, Y. & Inoue, K. Dynamic inhibition of excitatory synaptic transmission by astrocyte-derived ATP in hippocampal cultures. Proc. Natl Acad. Sci. USA 100, 11023–11028 (2003)
Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005)
Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nature Neurosci. 8, 752–758 (2005)
Honda, S. et al. Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. J. Neurosci. 21, 1975–1982 (2001)
Nasu-Tada, K., Koizumi, S. & Inoue, K. Involvement of β1 integrin in microglial chemotaxis and proliferation on fibronectin: different regulations by ADP through PKA. Glia 52, 98–107 (2005)
Ferrari, D. et al. P2Z purinoreceptor ligation induces activation of caspases with distinct roles in apoptotic and necrotic alterations of cell death. FEBS Lett. 447, 71–75 (1999)
Suzuki, T. et al. Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia. J. Neurosci. 24, 1–7 (2004)
Tsuda, M. et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783 (2003)
Chang, K., Hanaoka, K., Kumada, M. & Takuwa, Y. Molecular cloning and functional analysis of a novel P2 nucleotide receptor. J. Biol. Chem. 270, 26152–26158 (1995)
Communi, D., Parmentier, M. & Boeynaems, J. M. Cloning, functional expression and tissue distribution of the human P2Y6 receptor. Biochem. Biophys. Res. Commun. 222, 303–308 (1996)
Mamedova, L. K., Joshi, B. V., Gao, Z. G., von Kugelgen, I. & Jacobson, K. A. Diisothiocyanate derivatives as potent, insurmountable antagonists of P2Y6 nucleotide receptors. Biochem. Pharmacol. 67, 1763–1770 (2004)
Greenberg, S. Signal transduction of phagocytosis. Trends Cell Biol. 5, 93–99 (1995)
Mitchison, T. J. & Cramer, L. P. Actin-based cell motility and cell locomotion. Cell 84, 371–379 (1996)
Lauffenburger, D. A. & Horwitz, A. F. Cell migration: a physically integrated molecular process. Cell 84, 359–369 (1996)
Ohsawa, K., Imai, Y., Kanazawa, H., Sasaki, Y. & Kohsaka, S. Involvement of Iba1 in membrane ruffling and phagocytosis of macrophages/microglia. J. Cell Sci. 113, 3073–3084 (2000)
Kreutzberg, G. W. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312–318 (1996)
Nicholas, R. A. et al. Pharmacological and second messenger signalling selectivities of cloned P2Y receptors. J. Auton. Pharmacol. 16, 319–323 (1996)
Mellor, E. A., Maekawa, A., Austen, K. F. & Boyce, J. A. Cysteinyl leukotriene receptor 1 is also a pyrimidinergic receptor and is expressed by human mast cells. Proc. Natl Acad. Sci. USA 98, 7964–7969 (2001)
Lauber, K. et al. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113, 717–730 (2003)
Bard, F. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med. 6, 916–919 (2000)
Sperk, G. et al. Kainic acid induced seizures: neurochemical and histopathological changes. Neuroscience 10, 1301–1315 (1983)
Lazarowski, E. R., Homolya, L., Boucher, R. C. & Harden, T. K. Direct demonstration of mechanically induced release of cellular UTP and its implication for uridine nucleotide receptor activation. J. Biol. Chem. 272, 24348–24354 (1997)
Lazarowski, E. R., Shea, D. A., Boucher, R. C. & Harden, T. K. Release of cellular UDP-glucose as a potential extracellular signaling molecule. Mol. Pharmacol. 63, 1190–1197 (2003)
Erlinge, D. et al. Uridine triphosphate (UTP) is released during cardiac ischemia. Int. J. Cardiol. 100, 427–433 (2005)
Ravichandran, K. S. ‘Recruitment signals’ from apoptotic cells: invitation to a quiet meal. Cell 113, 817–820 (2003)
Nakajima, K. et al. Identification of elastase as a secretory protease from cultured rat microglia. J. Neurochem. 58, 1401–1408 (1992)
Lazarowski, E. R., Boucher, R. C. & Harden, T. K. Constitutive release of ATP and evidence for major contribution of ecto-nucleotide pyrophosphatase and nucleoside diphosphokinase to extracellular nucleotide concentrations. J. Biol. Chem. 275, 31061–31068 (2000)
We thank T. Shimizu and Dr. S. Ishii for providing CysLT1 receptor-expressed Chinese hamster ovary cells; K. Sakemi for technical assistance; Y. Sasaki for helpful suggestions; K. Suzuki and R. Adachi for allowing us to use the Pascal confocal microscope system; and T. Nishimaki-Mogami, Y. Ohno and T. Nagao for continuous encouragement. This study was supported in part by a grant from The National Institute of Biomedical Innovation, a grant from Uehara Memorial Foundation, a Grant-in-Aid for Scientific Research on Priority Areas, for Creative Scientific Research, Scientific Research (A and B), and for Young Scientists (A) from the Ministry of Education, Science, Sports and Culture of Japan.
Author Contributions S.K. designed most experiments, performed Ca2+ imaging and in vivo experiments and wrote the paper. Y.S.M. conducted major parts of the experiments. K.N.T. and Y.S. carried out the FACS assay and the HPLC analysis, respectively. K.O. and S.K. performed the chemotaxis analysis. B.V.J. and K.A.J. made the P2Y6 receptor antagonist MRS2578. M.T. analysed the data. K.I. analysed the data and coordinated the project. K.I. also designed the project. All authors discussed the results and commented on the manuscript.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
This file contains Supplementary Methods and Supplementary Figures 1-6 with Legends. (PDF 895 kb)
This file contains Supplementary Movie showing a time-lapse image of the effect of UDP on the microglial morphogenic changes and uptake of fluorescent zymozan particles (green). This Supplementary Movie corresponds to Fig. 2c in the manuscript. (MOV 776 kb)
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Koizumi, S., Shigemoto-Mogami, Y., Nasu-Tada, K. et al. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446, 1091–1095 (2007). https://doi.org/10.1038/nature05704
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