Inhibition of UDP/P2Y6 purinergic signaling prevents phagocytosis of viable neurons by activated microglia in vitro and in vivo.
Bottom Line: Furthermore, the P2Y6 receptor agonist UDP by itself was sufficient to stimulate microglial phagocytosis and to induce rapid neuronal loss that was prevented by eliminating microglia or inhibiting phagocytosis.In vivo, injection of LPS into rat striatum induced microglial activation and delayed neuronal loss and blocking P2Y6 receptors with MRS2578 prevented this neuronal loss.Thus, blocking UDP/P2Y6 signaling is sufficient to prevent neuronal loss and death induced by a wide range of stimuli that activate microglial phagocytosis of neurons.
Affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.Show MeSH
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Mentions: The endogenous agonist for P2Y6 receptors is thought to be UDP (Chang et al., 1995). Exogenous UDP (100 Î¼M) has previously been reported to promote microglial phagocytosis via P2Y6 activation (Koizumi et al., 2007) and we confirmed here that acute treatment of mixed glial cultures with 100 Î¼M UDP strongly enhanced microglial phagocytic activity as measured by their uptake of microbeads (1 or 5 Î¼m diameter and negatively charged, Fig. 4A).
Affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.