System xc− regulates microglia and macrophage glutamate excitotoxicity in vivo

► We show that CNS macrophages can cause neuronal excitotoxicity in vivo. ► Activated CNS microglia/macrophages exert divergent effects on neurons and glia. ► Demyelination, neuron loss and axon pathology cannot be predicted by the mere presence or absence of activated macrophages. ► The redox signature of CNS macrophages may regulate acute neuroinflammatory-mediated injury.