FTY720 requires vitamin B ₁₂ -TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis

Summary FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analogue approved for multiple sclerosis (MS) therapy, which can functionally antagonize the S1P receptor, S1P 1 . Vitamin B 12 (B 12 ) deficiency produces neurological manifestations resembling MS. Here, we report a new mechanism where FTY720 suppresses neuroinflammation by regulating B 12 metabolic pathways. Nuclear RNA-seq of c-Fos-activated astrocytes (called ieAstrocytes ) from experimental autoimmune encephalomyelitis (EAE) spinal cords identified up-regulation of CD320, a transcobalamin 2 (TCN2)-B 12 receptor, by S1P 1 inhibition. CD320 was reduced in MS plaques. Deficiency of CD320 or dietary B 12 worsened EAE and eliminated FTY720’s efficacy, while concomitantly down-regulating type I interferon signaling. TCN2 functioned as a chaperone for FTY720 and sphingosine, which induced astrocytic CD320 internalization. An accompanying paper identified a requirement for astrocyte sphingosine kinases in FTY720 efficacy and its altered expression in MS brains, molecularly linking MS and B 12 deficiency that can be accessed by sphingolipid/fingolimod metabolic pathways.