Transformation of Astrocytes to a Neuroprotective Phenotype by Microglia via P2Y₁ Receptor Downregulation

Microglia and astrocytes become reactive following traumatic brain injury (TBI). However, the coordination of this reactivity and its relation to pathophysiology are unclear. Here, we show that microglia transform astrocytes into a neuroprotective phenotype via downregulation of the P2Y₁ purinergic receptor. TBI initially caused microglial activation in the injury core, followed by reactive astrogliosis in the peri-injured region and formation of a neuroprotective astrocyte scar. Equivalent changes to astrocytes were observed in vitro after injury. This change in astrocyte phenotype resulted from P2Y₁ receptor downregulation, mediated by microglia-derived cytokines. In mice, astrocyte-specific P2Y₁ receptor overexpression (Astro-P2Y₁OE) counteracted scar formation, while astrocyte-specific P2Y₁ receptor knockdown (Astro-P2Y₁KD) facilitated scar formation, suggesting critical roles of P2Y₁ receptors in the transformation. Astro-P2Y₁OE and Astro-P2Y₁KD mice showed increased and reduced neuronal damage, respectively. Altogether, our findings indicate that microglia-astrocyte interaction, involving a purinergic signal, is essential for the formation of neuroprotective astrocytes.