Schubert C, Lopes Fonseca R, Hadjilaou A, Vieira V, Degenhardt K, Seemann AL, Hakimy A, Sonner JK, Ludewig P, Magnus T, Schneider M, Müller CE, Hirnet D, Friese MA.
Extracellular adenosine triphosphate (ATP) and diphosphate (ADP) act as key signalling molecules in the central nervous system (CNS) and regulate neuroinflammatory responses through purinergic receptors. Although astrocytes and neurons undergo profound changes in signalling and metabolism during inflammation, the contribution of specific purinergic pathways to inflammation-induced neurodegeneration remains unclear. Here we show that the ADP/ATP-activated Gq-coupled receptor P2Y1 drives astrocyte-mediated neurotoxicity in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Using plasma membrane-targeted luciferase reporter mice, we demonstrate that extracellular ATP levels are increased during acute EAE. This was accompanied by elevated astrocytic P2ry1 expression, which is also observed in inflammatory MS lesions. In vivo, pharmacological inhibition or astrocyte-specific deletion of P2Y1 reduced disease severity, astrocytosis, and neuronal loss, whereas neuron-specific deletion exerted only modest effects. Mechanistically, astrocytic P2Y1 signalling promoted cytokine-induced ERK activation, inflammatory gene expression, and metabolic reprogramming in vitro. In contrast to supernatants from stimulated P2Y1-deficient astrocyte culture, supernatants derived from stimulated P2Y1-proficient astrocytes reduced neuronal viability, demonstrating neurotoxic effects mediated by astrocyte-derived factors. In contrast, neuronal P2Y1 signalling primarily contributed to oxidative stress and mitochondrial dysfunction. Together, these findings identify astrocytic P2Y1 as a key regulator of neuroinflammatory damage and a potential therapeutic target.J Neuroinflammation. 2026 Jun 13;23(1):199
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