Astrocytes play complex roles in the response to trauma, infection or inflammation in the central nervous system (CNS). Thus, it is important to characterize the mechanisms regulating astrocyte function, as well as potential targets for the therapeutic modulation of astrocyte activity. Here we report that lactosylceramide (LacCer) levels are up-regulated in the CNS during chronic experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). We found that LacCer synthesized by β-1,4-galactosyltransferase 6 (B4GALT6) in astrocytes acts in an autocrine manner to trigger transcriptional programs that promote the recruitment and activation of CNS-infiltrating monocytes and microglia, and neurodegeneration. We also detected increased B4GALT6 expression and LacCer levels in CNS MS lesions. Finally, the inhibition of LacCer synthesis suppressed local CNS innate immunity and neurodegeneration in EAE, and interfered with the activation of human astrocytes in vitro . Thus, B4GALT6 is a potential therapeutic target for MS and other neuroinflammatory disorders.