Koizumi, S. et al. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446, 1091-1095

Division of Pharmacology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
Nature (Impact Factor: 41.46). 05/2007; 446(7139):1091-5. DOI: 10.1038/nature05704
Source: PubMed


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.

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    • "As opposed to the hippocampus, where P2Y6 colocalizes with activated microglia (Koizumi et al., 2007), in the ARH of lean mice, we identify P2Y6 as being specifically expressed in neurons, providing evidence for a region-dependent, cell-type-specific expression pattern of P2Y6 in the CNS. Guided by the microglial expression of P2Y6, previous studies had mostly focused on the microglial role of P2Y6, where P2Y6 signaling was demonstrated to activate microglia and to promote phagocytosis (Koizumi et al., 2007). Here, we show that, in contrast, P2Y6 directly activates AgRP neurons in the ARH to potently promote feeding, while it only has minor effects on the activation of anorexigenic POMC neurons. "
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    ABSTRACT: Activation of orexigenic AgRP-expressing neurons in the arcuate nucleus of the hypothalamus potently promotes feeding, thus defining new regulators of AgRP neuron activity could uncover potential novel targets for obesity treatment. Here, we demonstrate that AgRP neurons express the purinergic receptor 6 (P2Y6), which is activated by uridine-diphosphate (UDP). In vivo, UDP induces ERK phosphorylation and cFos expression in AgRP neurons and promotes action potential firing of these neurons in brain slice recordings. Consequently, central application of UDP promotes feeding, and this response is abrogated upon pharmacologic or genetic inhibition of P2Y6 as well as upon pharmacogenetic inhibition of AgRP neuron activity. In obese animals, hypothalamic UDP content is elevated as a consequence of increased circulating uridine concentrations. Collectively, these experiments reveal a potential regulatory pathway in obesity, where peripheral uridine increases hypothalamic UDP concentrations, which in turn can promote feeding via PY6-dependent activation of AgRP neurons.
    Cell 09/2015; 162(6):1404-1417. DOI:10.1016/j.cell.2015.08.032 · 32.24 Impact Factor
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    • "In a Japanese genomic analysis, a specific P2Y2 haplotype was associated with an increased risk of arteriosclerosis and cerebral infarction, especially in women (Wang et al., 2009). However, P2Y2R and P2Y6R both promote the phagocytic clearance of apoptotic cells or bacteria, thereby contributing to the termination of inflammation (Koizumi et al., 2007), but endothelial or epithelial expression of P2Y6R can also play a role in innate immune activation (Riegel et al., 2011). The fact that P2Y12R is important for platelet activation and aggregation is useful for antithrombotic therapy in patients by P2Y12R antagonists clopidogrel and ticagrelor. "
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    ABSTRACT: Danger molecules are the first signals released from dying tissue after stroke. These danger signals bind to receptors on immune cells that will result in their activation and the release of inflammatory and neurotoxic mediators, resulting in amplification of the immune response and subsequent enlargement of the damaged brain volume. The release of danger signals is a central event that leads to a multitude of signals and cascades in the affected and neighbouring tissue, therefore providing a potential target for therapy. Copyright © 2015. Published by Elsevier B.V.
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    • "restoring the CNS steady state (Koizumi et al., 2007; Sierra et al., 2010). Developmental studies show that microglia arise on embryonic day 8.5 from early yolk-sac-derived precursors (Ginhoux et al., 2010) that have erythro-myeloid potential. "
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    ABSTRACT: During early embryogenesis, microglia arise from yolk sac progenitors that populate the developing central nervous system (CNS), but how the tissue-resident macrophages are maintained throughout the organism's lifespan still remains unclear. Here, we describe a system that allows specific, conditional ablation of microglia in adult mice. We found that the microglial compartment was reconstituted within 1 week of depletion. Microglia repopulation relied on CNS-resident cells, independent from bone-marrow-derived precursors. During repopulation, microglia formed clusters of highly proliferative cells that migrated apart once steady state was achieved. Proliferating microglia expressed high amounts of the interleukin-1 receptor (IL-1R), and treatment with an IL-1R antagonist during the repopulation phase impaired microglia proliferation. Hence, microglia have the potential for efficient self-renewal without the contribution of peripheral myeloid cells, and IL-1R signaling participates in this restorative proliferation process. Copyright © 2015 Elsevier Inc. All rights reserved.
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