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 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.

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…This process may be important under conditions of neuronal damage. UDP, leaking out from damaged hippocampal cells facilitates the uptake of cellular debris by microglia in a P2Y 6 -dependent manner (Koizumi et al, 2007).…”

Physiological and pathological functions of P2X7 receptor in the spinal cord

“…ATP released from damaged neurons could stimulate ATP-dependent astrocytic calcium waves that, in turn, could affect neuronal, microglial and endothelial responses. Furthermore, ATP released from damaged neurons functions as chemotactile cue for microglia, which in turn can initiate inflammatory responses and phagocytosis [83]. Very promising therapeutic results have recently been obtained with compounds like the P2X7R antagonist oATP, which reduces neuronal cell death and improves functional recovery in a rat model of spinal cord injury [14], and the P2X4R modulator ivermectin, which promotes motoneuron survival in a model for amyotrophic lateral sclerosis [84].…”

IRF8 is a transcriptional determinant for microglial motility

“…Once abnormalities are detected, microglia dramatically transform into a reactive phenotype through a progressive series of cellular and molecular changes, including morphological hypertrophy, proliferation, and the expression of various genes [3,5]. Following these changes, activated microglia destroy infectious agents, remove cell debris, and promote tissue repair [1,6,7], that is, microglia form the first line of defense in the CNS. When acute injuries occur in the brain or spinal cord, microglia densely extend their processes toward the lesion site within several minutes [8,9], or migrate to the site [10], by which they prevent the spread of the lesion.…”