Inhibition of UDP/P2Y6 purinergic signaling prevents phagocytosis of viable neurons by activated microglia in vitro and in vivo.
Bottom Line: We find that delayed neuronal loss and death in mixed neuronal/glial cultures induced by the TLR ligands lipopolysaccharide (LPS) or lipoteichoic acid was prevented by: apyrase (to degrade nucleotides), Reactive Blue 2 (to inhibit purinergic signaling), or MRS2578 (to specifically block P2Y6 receptors).In each case, inflammatory activation of microglia was not affected, and the rescued neurons remained viable for at least 7 days.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.
Affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.Show MeSH
Related in: MedlinePlus
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.