Inhibition of P2Y6 Receptor-Mediated Microglia Phagocytosis Aggravates Brain Injury in Mice of Intracerebral Hemorrhage.

Abstract

Intracerebral hemorrhage (ICH) is a devastating stroke subtype leading to severe sensorimotor dysfunction. Many studies showed that microglia phagocytosis could promote hematoma absorption, and scavenger receptors expressed on microglia were associated with its phagocytosis. As a specific phagocytic receptor, blocking the P2Y6 receptor (P2Y6R) with MRS2578 (3 mg/kg) could inhibit the phagocytic activity of microglia, which had been reported in a variety of neurological disorders, such as cerebral ischemia, Parkinson's diseases and neurodegenerative diseases. But the effects of P2Y6R-mediated microglia phagocytosis on the prognosis of ICH are still lacking. In the present study, we showed that P2Y6R expression elevated and peaked at day 3 after ICH. And treatment with MRS2578 (3 mg/kg) for three consecutive days could impair the phagocytosis of microglia, accompanied by delayed hematoma absorption rate, aggravated brain edema and blood-brain barrier disruption, as well as impaired neurological deficit in ICH mice. MRS2578 treatment also increased the expression of pro-inflammatory factors (TNF-α, iNOS) after ICH. Furthermore, MRS2578 treatment further increased the expression of NF-κB, which regulates the expression of these pro-inflammatory cytokines. In summary, our results suggested that regulating microglial phagocytosis could improve the prognosis of ICH, and P2Y6R offered a meaningful target.