Nature：一种新型的微型神经胶质噬菌作用

Nature 446, 1091-1095 (26 April 2007) | doi:10.1038/nature05704; Received 23 December 2006; Accepted 23 February 2007; Published online 4 April 2007

UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis

Schuichi Koizumi1,2,6, Yukari Shigemoto-Mogami1,6, Kaoru Nasu-Tada1, Yoichi Shinozaki1,3, Keiko Ohsawa4, Makoto Tsuda3, Bhalchandra V. Joshi5, Kenneth A. Jacobson5, Shinichi Kohsaka4 & Kazuhide Inoue3

1. Division of Pharmacology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan
2. Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3893, Japan
3. Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka 812-8582, Japan
4. Department of Neurochemistry, National Institute of Neuroscience, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan
5. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0810, USA
6. These authors contributed equally to this work.

Correspondence to: Kazuhide Inoue3 Correspondence and requests for materials should be addressed to K.I. (Email: inoue@phar.kyushu-u.ac.jp).

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 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.