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
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Mentions: We found here (summarized in Fig. 6) that the neuronal loss induced by LPS or LTA was prevented by: (i) delayed addition of extracellular apyrase, which degrades nucleoside triphosphates and diphosphates, indicating that extracellular nucleoside triphosphates or diphosphates are required for neuronal loss, (ii) RB2, which nonspecifically inhibits purinergic receptors, indicating that purinergic signaling is required for neuronal loss, and (iii) MRS2578, which specifically blocks P2Y6 receptors, indicating that activation of these receptors is required for neuronal loss. Blocking P2Y6 receptors with MRS2578 also prevented phagoptosis of neurons induced by Aβ1–42 and peroxynitrite (authentic or when produced from the degradation of SIN-1). Furthermore, in vivo injection of LPS into rat striatum induced microglial activation and delayed neuronal loss that was prevented by blocking P2Y6 receptors with MRS2578. Thus, blocking UDP/P2Y6 signaling is sufficient to prevent neuronal loss and death induced by a wide range of stimuli activating microglial phagocytosis of neurons. It will be important to test whether this is beneficial in animal models of neurological disease.
Affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.