UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis

Schuichi Koizumi, Yukari Shigemoto-Mogami, Kaoru Nasu-Tada, Yoichi Shinozaki, Keiko Ohsawa, Makoto Tsuda, Bhalchandra V. Joshi, Kenneth A. Jacobson, Shinichi Kohsaka, Kazuhide Inoue

Research output: Contribution to journalArticle

440 Citations (Scopus)

Abstract

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 P2Y 6 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.

Original languageEnglish
Pages (from-to)1091-1095
Number of pages5
JournalNature
Volume446
Issue number7139
DOIs
Publication statusPublished - Apr 26 2007

Fingerprint

Uridine Diphosphate
Microglia
Phagocytosis
Kainic Acid
Adenosine Triphosphate
Hippocampal CA3 Region
Hippocampal CA1 Region
Neurons
Brain
Chemotaxis
Microspheres
purinoceptor P2Y6
Cell Death
Nucleotides
Maintenance
Messenger RNA

All Science Journal Classification (ASJC) codes

  • General

Cite this

Koizumi, S., Shigemoto-Mogami, Y., Nasu-Tada, K., Shinozaki, Y., Ohsawa, K., Tsuda, M., ... Inoue, K. (2007). UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature, 446(7139), 1091-1095. https://doi.org/10.1038/nature05704

UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. / Koizumi, Schuichi; Shigemoto-Mogami, Yukari; Nasu-Tada, Kaoru; Shinozaki, Yoichi; Ohsawa, Keiko; Tsuda, Makoto; Joshi, Bhalchandra V.; Jacobson, Kenneth A.; Kohsaka, Shinichi; Inoue, Kazuhide.

In: Nature, Vol. 446, No. 7139, 26.04.2007, p. 1091-1095.

Research output: Contribution to journalArticle

Koizumi, S, Shigemoto-Mogami, Y, Nasu-Tada, K, Shinozaki, Y, Ohsawa, K, Tsuda, M, Joshi, BV, Jacobson, KA, Kohsaka, S & Inoue, K 2007, 'UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis', Nature, vol. 446, no. 7139, pp. 1091-1095. https://doi.org/10.1038/nature05704
Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M et al. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature. 2007 Apr 26;446(7139):1091-1095. https://doi.org/10.1038/nature05704
Koizumi, Schuichi ; Shigemoto-Mogami, Yukari ; Nasu-Tada, Kaoru ; Shinozaki, Yoichi ; Ohsawa, Keiko ; Tsuda, Makoto ; Joshi, Bhalchandra V. ; Jacobson, Kenneth A. ; Kohsaka, Shinichi ; Inoue, Kazuhide. / UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. In: Nature. 2007 ; Vol. 446, No. 7139. pp. 1091-1095.
@article{05f1fed2e6244b8ebe470986caab2d81,
title = "UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis",
abstract = "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 P2Y 6 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.",
author = "Schuichi Koizumi and Yukari Shigemoto-Mogami and Kaoru Nasu-Tada and Yoichi Shinozaki and Keiko Ohsawa and Makoto Tsuda and Joshi, {Bhalchandra V.} and Jacobson, {Kenneth A.} and Shinichi Kohsaka and Kazuhide Inoue",
year = "2007",
month = "4",
day = "26",
doi = "10.1038/nature05704",
language = "English",
volume = "446",
pages = "1091--1095",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7139",

}

TY - JOUR

T1 - UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis

AU - Koizumi, Schuichi

AU - Shigemoto-Mogami, Yukari

AU - Nasu-Tada, Kaoru

AU - Shinozaki, Yoichi

AU - Ohsawa, Keiko

AU - Tsuda, Makoto

AU - Joshi, Bhalchandra V.

AU - Jacobson, Kenneth A.

AU - Kohsaka, Shinichi

AU - Inoue, Kazuhide

PY - 2007/4/26

Y1 - 2007/4/26

N2 - 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 P2Y 6 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.

AB - 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 P2Y 6 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.

UR - http://www.scopus.com/inward/record.url?scp=34247637676&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34247637676&partnerID=8YFLogxK

U2 - 10.1038/nature05704

DO - 10.1038/nature05704

M3 - Article

C2 - 17410128

AN - SCOPUS:34247637676

VL - 446

SP - 1091

EP - 1095

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7139

ER -