Journal Article

UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis

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

2007

Overview

Keeping things tidy Phagocytosis is thought to be initiated by activation of phagocytosis-promoting receptors that recognize 'eat-me' signals such as phosphatidylserine or amyloid-β expressed in the apoptotic cells. But now Koizumi et al . demonstrate a novel type of microglial phagocytosis that requires neither typical 'eat-me' signals nor Fc receptor ligands for initiation. Instead, this phagocytosis is promoted by the diffusible extracellular molecule uridine 5′-diphosphate, released by injured cells. The UDP activates P2Y 6 receptors on the microglial surface. The clearance of dead cells is crucial to the maintenance of brain function, so these findings may have implications for a range of central nervous system diseases. 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 1 , 2 or injured 3 , 4 , extracellular nucleotides are thought to be involved in these events. In fact, ATP triggers a dynamic change in the motility of microglia in vitro 5 , 6 and in vivo 3 , 4 , a previously unrecognized mechanism underlying microglial chemotaxis 5 , 6 ; 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 P2Y 6 -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 P2Y 6 receptors that colocalized with activated microglia were observed. Thus, the P2Y 6 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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Adenosine triphosphatase / Adenosinic and purinergic receptors / Animals / ATP / Biochemistry / Biological and medical sciences / Brain / Calcium - metabolism / Calcium Signaling - drug effects / Cell Death - drug effects / Cell Movement - drug effects / Cell receptors / Cell structures and functions / Cellular biology / Fundamental and applied biological sciences. Psychology / Hippocampus - cytology / Hippocampus - drug effects / Hippocampus - metabolism / Humanities and Social Sciences / Kainic Acid - pharmacology / letter / Microglia - cytology / Microglia - drug effects / Microglia - immunology / Microglia - metabolism / Molecular and cellular biology / multidisciplinary / Neurosciences / Phagocytosis - drug effects / Rats / Receptors, Purinergic P2 - metabolism / Ribonucleic acid / RNA / Rodents / Science / Science (multidisciplinary) / Uridine - metabolism / Uridine Diphosphate - metabolism / Uridine Diphosphate - pharmacology