UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis
Open accessAbstract
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 stimulated or injured, extracellular nucleotides are thought to be involved in these events. In fact, ATP triggers a dynamic change in the motility of microglia in vitro and in vivo, a previously unrecognized mechanism underlying microglial chemotaxis; 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ATP released from dying cells activates macrophages and may be required for immunogenicity of dying tumor cells.
“Indeed, ATP, which is released from dying cells and activates macrophages 44, may also be required for the immunogenicity of dying tumor cells (L.Z. and G.K., unpublished observations).”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [44]
Potential immunogenic signals from dying cells include surface-exposed proteins such as calreticulin and heat shock proteins, lipid moieties such as phosphatidylserine that flip to the outer leaflet, released proteins such as HMGB1, and extracellular nucleic acids and their degradation products (oligonucleotides, nucleotides, nucleosides, urate).
“Potential immunogenic signals emanating from dying cells include proteins that appear at the surface of stressed and dying cells (such as calreticulin and heat shock proteins, HSPs), lipid moieties that flip from the inner plasma membrane leaflet to the outer leaflet (such as phosphatidylserine) 38,60, proteins that are released into the supernatant of cells (such as HMGB1) 51, as well as nucleic”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [44]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827 · see citing works
Microglia: a sensor for pathological events in the CNS
Kreutzberg, G. W. (1996) · Trends in Neurosciences · doi:10.1016/0166-2236(96)10049-7 · Cited by 4,396 · see citing works
Cell Migration: A Physically Integrated Molecular Process
Lauffenburger, D. A., & Horwitz, A. F. (1996) · Cell · doi:10.1016/s0092-8674(00)81280-5 · Cited by 3,915 · see citing works
ATP mediates rapid microglial response to local brain injury in vivo
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., & Gan, W.-B. (2005) · Nature Neuroscience · doi:10.1038/nn1472 · Cited by 3,913 · see citing works
Bard, F., Cannon, C., Barbour, R., Burke, R.-L., Games, D., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., et al. (2000) · Nature Medicine · doi:10.1038/78682 · Cited by 2,012 · see citing works
P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury
Tsuda, M., Shigemoto‐Mogami, Y., Koizumi, S., Mizokoshi, A., Kohsaka, S., Salter, M. W., & Inoue, K. (2003) · Nature · doi:10.1038/nature01786 · Cited by 1,567 · see citing works
Self-citationActin-Based Cell Motility and Cell Locomotion
Mitchison, T. J., & Cramer, L. P. (1996) · Cell · doi:10.1016/s0092-8674(00)81281-7 · Cited by 1,538 · see citing works
Lauber, K., Bohn, E., Kröber, S. M., Xiao, Y.-J., Blumenthal, S. G., Lindemann, R. K., Marini, P., Wiedig, C., Zobywalski, A., Baksh, S., et al. (2003) · Cell · doi:10.1016/s0092-8674(03)00422-7 · Cited by 967 · see citing works
ATP Released from Astrocytes Mediates Glial Calcium Waves
Guthrie, P. B., Knappenberger, J., Segal, M., Bennett, M. V. L., Charles, A. C., & Kater, S. B. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-02-00520.1999 · Cited by 806 · see citing works
Honda, S., Sasaki, Y., Ohsawa, K., Imai, Y., Nakamura, Y., Inoue, K., & Kohsaka, S. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-06-01975.2001 · Cited by 561 · see citing works
Self-citationKainic acid induced seizures: Neurochemical and histopathological changes
Sperk, G., Lassmann, H., Baran, H., Kish, S. J., SEITELBERGER, F., & Hornykiewicz, O. (1983) · Neuroscience · doi:10.1016/0306-4522(83)90113-6 · Cited by 529 · see citing works
Involvement of Iba1 in membrane ruffling and phagocytosis of macrophages/microglia
Ohsawa, K., Imai, Y., Kanazawa, H., Sasaki, Y., & Kohsaka, S. (2000) · Journal of Cell Science · doi:10.1242/jcs.113.17.3073 · Cited by 420 · see citing works
Self-citationSuzuki, T., Hide, I., Ido, K., Kohsaka, S., Inoue, K., & Nakata, Y. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.3792-03.2004 · Cited by 394 · see citing works
Self-citationLazarowski, E. R., Boucher, R. C., & Harden, T. K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003255200 · Cited by 316 · see citing works
Lazarowski, E. R., Homolya, L., Boucher, R. C., & Harden, T. K. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.39.24348 · Cited by 286 · see citing works
Ferrari, D., Łoś, M., Bauer, M. K. A., Vandenabeele, P., Wesselborg, S., & Schulze‐Osthoff, K. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00270-7 · Cited by 276 · see citing works
Cloning, Functional Expression and Tissue Distribution of the Human P2Y6Receptor
Communi, D., Parmentier, M., & Boeynaems, J. (1996) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1996.0739 · Cited by 260 · see citing works
Koizumi, S., Fujishita, K., Tsuda, M., Shigemoto‐Mogami, Y., & Inoue, K. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834448100 · Cited by 250 · see citing works
Self-citationMolecular Cloning and Functional Analysis of a Novel P2 Nucleotide Receptor
Chang, K., Hanaoka, K., Kumada, M., & Takuwa, Y. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.44.26152 · Cited by 249 · see citing works
Signal transduction of phagocytosis
Greenberg, S. (1995) · Trends in Cell Biology · doi:10.1016/s0962-8924(00)88957-6 · Cited by 183 · see citing works
Mellor, E. A., Maekawa, A., Austen, K. F., & Boyce, J. A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141221498 · Cited by 179 · see citing works
Diisothiocyanate derivatives as potent, insurmountable antagonists of P2Y6 nucleotide receptors
Mamedova, L. K., Joshi, B. V., Gao, Z., et al. (2004) · Biochemical Pharmacology · doi:10.1016/j.bcp.2004.01.011 · Cited by 168 · see citing works
Self-citation“Recruitment Signals” from Apoptotic Cells
Ravichandran, K. S. (2003) · Cell · doi:10.1016/s0092-8674(03)00471-9 · Cited by 154 · see citing works
Release of Cellular UDP-Glucose as a Potential Extracellular Signaling Molecule
Lazarowski, E. R., Shea, D. A., Boucher, R. C., & Harden, T. K. (2003) · Molecular Pharmacology · doi:10.1124/mol.63.5.1190 · Cited by 147 · see citing works
Identification of Elastase as a Secretory Protease from Cultured Rat Microglia
Nakajima, K., Shimojo, M., Hamanoue, M., Ishiura, S., Sugita, H., & Kohsaka, S. (1992) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1992.tb11356.x · Cited by 139 · see citing works
Self-citationNasu‐Tada, K., Koizumi, S., & Inoue, K. (2005) · Glia · doi:10.1002/glia.20224 · Cited by 100 · see citing works
Self-citationPharmacological and second messenger signalling selectivities of cloned P2Y receptors
Nicholas, R. A., Lazarowski, E. R., Watt, W. C., et al. (1996) · Journal of Autonomic Pharmacology · doi:10.1111/j.1474-8673.1996.tb00044.x · Cited by 76 · see citing works
Uridine triphosphate (UTP) is released during cardiac ischemia
Erlinge, D., Harnek, J., van Heusden, C. A., Olivecrona, G. K., Jern, S., & Lazarowski, E. R. (2005) · International Journal of Cardiology · doi:10.1016/j.ijcard.2004.10.005 · Cited by 51 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Microglial physiology: unique stimuli, specialized responses
Ransohoff, R. M., & Perry, V. H. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132528 · Cited by 1,858 · see citing works
Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance
Elliott, M. R., Chekeni, F. B., Trampont, P. C., Lazarowski, E. R., Kadl, A., Walk, S. F., Park, D., Woodson, R. I., Ostankovich, M., Sharma, P., et al. (2009) · Nature · doi:10.1038/nature08296 · Cited by 1,654 · see citing works
Immunogenic and tolerogenic cell death
Green, D. R., Ferguson, T., Zitvogel, L., & Kroemer, G. (2009) · Nature Reviews Immunology · doi:10.1038/nri2545 · Cited by 1,176 · see citing works
Debris clearance by microglia: an essential link between degeneration and regeneration
Neumann, H., Kotter, M. R., & Franklin, R. J. M. (2008) · Brain · doi:10.1093/brain/awn109 · Cited by 1,111 · see citing works
Microglial cell origin and phenotypes in health and disease
Saijo, K., & Glass, C. K. (2011) · Nature Reviews Immunology · doi:10.1038/nri3086 · Cited by 1,100 · see citing works
Microglial Phagocytosis of Live Neurons
Brown, G. C., & Neher, J. J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3710 · Cited by 853 · see citing works
Inflammation and neuroprotection in traumatic brain injury.
Corps, K. N., Roth, T. L., & McGavern, D. B. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2014.3558 · Cited by 853 · see citing works
Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift
Jassam, Y. N., Izzy, S., Whalen, M., McGavern, D. B., & El Khoury, J. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.010 · Cited by 799 · see citing works
Neuronal ‘On’ and ‘Off’ signals control microglia
Biber, K., Neumann, H., Inoue, K., & Boddeke, H. W. G. M. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.08.007 · Cited by 787 · see citing works
Self-citationBruttger, J., Karram, K., Wörtge, S., Regen, T., Marini, F., Hoppmann, N., Klein, M., Blank, T., Yona, S., Wolf, Y., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.06.012 · Cited by 634 · see citing works
Neurotransmitter receptors on microglia
Pocock, J. M., & Kettenmann, H. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.07.007 · Cited by 650 · see citing works
Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis
Sierra, A., Abiega, O., Shahraz, A., & Neumann, H. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00006 · Cited by 574 · see citing works
The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma.
Ramirez, A. I., de Hoz, R., Salobrar-Garcia, E., Salazar, J. J., Rojas, B., Ajoy, D., López-Cuenca, I., Rojas, P., Triviño, A., & Ramírez, J. M. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00214 · Cited by 466 · see citing works
González, H., Elgueta, D., Montoya, A., & Pacheco, R. (2014) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2014.07.012 · Cited by 352 · see citing works
Microglia Phenotypes in Aging and Neurodegenerative Diseases
Wendimu, M. Y., & Hooks, S. B. (2022) · Cells · doi:10.3390/cells11132091 · Cited by 336 · see citing works
Danger signals in stroke and their role on microglia activation after ischemia
Gülke, E., Gelderblom, M., & Magnus, T. (2018) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756286418774254 · Cited by 321 · see citing works
Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity
Victor, M. B., Leary, N., Luna, X., Meharena, H. S., Scannail, A. N., Bozzelli, P. L., Samaan, G., Murdock, M. H., von Maydell, D., Effenberger, A. H., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.07.005 · Cited by 316 · see citing works
Arcuri, C., Mecca, C., Bianchi, R., Giambanco, I., & Donato, R. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00191 · Cited by 279 · see citing works
How microglia sense and regulate neuronal activity
Umpierre, A. D., & Wu, L. (2021) · Glia · doi:10.1002/glia.23961 · Cited by 237 · see citing works
A distinct population of microglia supports adult neurogenesis in the subventricular zone
Ribeiro Xavier, A. L., Kress, B. T., Goldman, S. A., Lacerda de Menezes, J. R., & Nedergaard, M. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.1217-15.2015 · Cited by 225 · see citing works
Functional Studies of Missense TREM2 Mutations in Human Stem Cell-Derived Microglia
Brownjohn, P. W., Smith, J., Solanki, R., Lohmann, E., Houlden, H., Hardy, J., Dietmann, S., & Livesey, F. J. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.03.003 · Cited by 193 · see citing works
Microglial immune checkpoint mechanisms
Deczkowska, A., Amit, I., & Schwartz, M. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0145-x · Cited by 185 · see citing works
Functions of microglia in the central nervous system—beyond the immune response
Wake, H., Moorhouse, A. J., & Nabekura, J. (2011) · Neuron Glia Biology · doi:10.1017/s1740925x12000063 · Cited by 167 · see citing works
Xie, M., Liu, Y. U., Zhao, S., Zhang, L., Bosco, D. B., Pang, Y.-P., Zhong, J., Sheth, U., Martens, Y. A., Zhao, N., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-021-00975-6 · Cited by 157 · see citing works
P2X7 receptor activation induces CXCL2 production in microglia through NFAT and PKC/MAPK pathways
Shiratori, M., Tozaki‐Saitoh, H., Yoshitake, M., Tsuda, M., & Inoue, K. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06809.x · Cited by 153 · see citing works
Self-citationShi, Y., Andhey, P. S., Ising, C., Wang, K., Snipes, L. L., Boyer, K., Lawson, S., Yamada, K., Qin, W., Manis, M., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.05.034 · Cited by 135 · see citing works
The endocytic pathway in microglia during health, aging and Alzheimer’s disease
Solé-Domènech, S., Cruz, D. L., Capetillo-Zarate, E., & Maxfield, F. R. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.07.002 · Cited by 133 · see citing works
Brown, G. C. (2024) · Nature Reviews Immunology · doi:10.1038/s41577-023-00921-6 · Cited by 129 · see citing works
Kataoka, A., Tozaki‐Saitoh, H., Koga, Y., Tsuda, M., & Inoue, K. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05744.x · Cited by 121 · see citing works
Self-citationReceptors, Ion Channels, and Signaling Mechanisms Underlying Microglial Dynamics
Madry, C., & Attwell, D. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.637157 · Cited by 109 · see citing works
“This allows them to interact physiologically with cells in the brain parenchyma, as well as respond promptly to brain damage or injury (4, 5) and clear cellular debris or accumulating metabolic products by phagocytosis (6).”
BackgroundMicroglia and intractable chronic pain
Tsuda, M., Beggs, S., Salter, M. W., & Inoue, K. (2013) · Glia · doi:10.1002/glia.22379 · Cited by 113 · see citing works
Self-citationDe Simone, R., Niturad, C. E., De Nuccio, C., Ajmone‐Cat, M. A., Visentin, S., & Minghetti, L. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06937.x · Cited by 104 · see citing works
Aging and sex: Impact on microglia phagocytosis
Yanguas‐Casás, N., Crespo‐Castrillo, A., Arevalo, M., & Garcia‐Segura, L. M. (2020) · Aging Cell · doi:10.1111/acel.13182 · Cited by 93 · see citing works
De Haas, A. H., Boddeke, H. W. G. M., Brouwer, N., & Biber, K. (2007) · Glia · doi:10.1002/glia.20554 · Cited by 81 · see citing works
Bottelbergs, A., Verheijden, S., Van Veldhoven, P. P., Just, W., Devos, R., & Baes, M. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-61 · Cited by 66 · see citing works
Expression of Tau40 Induces Activation of Cultured Rat Microglial Cells
Wang, L., Jiang, Q., Chu, J., Lin, L., Li, X.-G., Chai, G.-S., Wang, Q., Wang, J.-Z., & Tian, Q. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076057 · Cited by 47 · see citing works
Microglia phagocytic mechanisms: Development informing disease
Beiter, R. M., Sheehan, P. W., & Schafer, D. P. (2024) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2024.102877 · Cited by 44 · see citing works
Cytokine Signalling at the Microglial Penta-Partite Synapse
Aramideh, J. A., Vidal-Itriago, A., Morsch, M., & Graeber, M. B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413186 · Cited by 35 · see citing works
Lack of specificity shown by P2Y6 receptor antibodies
Yu, W., & Hill, W. G. (2013) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/s00210-013-0894-8 · Cited by 36 · see citing works
Microglial phagocytosis in Alzheimer disease
Brown, G. C., St George-Hyslop, P., Paolicelli, R. C., & Lemke, G. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-025-01162-y · Cited by 36 · see citing works
Ernest James Phillips, T., & Maguire, E. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.652593 · Cited by 33 · see citing works
Reynolds, K. E., Huang, E., Sabbineni, M., Wiseman, E., Murtaza, N., Ahuja, D., Napier, M., Murphy, K. M., Singh, K. K., & Scott, A. L. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04181-w · Cited by 6 · see citing works
- Authors
- Koizumi, S., Shigemoto-Mogami, Y., Nasu-Tada, K., Shinozaki, Y., Ohsawa, K., Tsuda, M., Joshi, B. V., Jacobson, K. A., Kohsaka, S., & Inoue, K.
- Affiliations
- National Institute of Health Sciences (JP)
- Kyushu University (JP)
- National Institute of Neuroscience (JP)
- National Institutes of Health (US)
- Corresponding author
- Inoue, Kazuhide
- Venue
- Nature
- Published
- 2007-04
- Volume
- 446
- Issue
- 7139
- Pages
- 1091-1095
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3464483
- OpenAlex
- W2011221727
- Cited by
- 802
- References
- 28
- Citations by year
- 2026: 28 · 2025: 34 · 2024: 44 · 2023: 40 · 2022: 47 · 2021: 58 · 2020: 60 · 2019: 32 · 2018: 41 · 2017: 38 · 2016: 36 · 2015: 41 · 2014: 50 · 2013: 42 · 2012: 48
- FWCI
- 20.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (Z01DK031116)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- microglial phagocytosis, P2Y6 receptor, UDP, purinergic signaling, microglia, neuronal injury, kainic acid, hippocampal neurons, extracellular nucleotides, ATP, microglial chemotaxis, neuroinflammation
- MeSH terms
- Animals, Calcium, Cell Movement, Hippocampus, Kainic Acid, Phagocytosis, Uridine, Uridine Diphosphate, Cell Death, Microglia, Receptors, Purinergic P2, Calcium Signaling, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
