Nature：一种新型的微型神经胶质噬菌作用
噬菌作用被认为是由能够启动噬菌作用的受体的激发启动的，这些受体能够识别出在凋亡细胞中所表达的"磷脂酰丝氨酸或淀粉质"这样的"来吃我吧"信号。但是现在，Koizumi等人发现了一种新型的微型神经胶质噬菌作用，它既不需要典型的来"吃我吧"信号，也不需要启动噬菌作用所需的Fc受体配体。相反，这一噬菌作用是由可扩散的细胞外分子"尿苷5’-二磷酸"（UDP）来启动的，而这种细胞外分子是由受伤的细胞释放的。UDP激发微型神经胶质表面上的P2Y6受体。死亡细胞的清除对于维护脑功能非常关键，所以这些发现也许对研究一系列中枢神经系统疾病都有意义。
英文原文:
Letter
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
- Division of Pharmacology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan
- Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3893, Japan
- Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka 812-8582, Japan
- Department of NeuRochemistry, National Institute of Neuroscience, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan
- 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
- 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.
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