FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis

Abstract

Vitamin B₁₂ (B₁₂) deficiency causes neurological manifestations resembling multiple sclerosis (MS); however, a molecular explanation for the similarity is unknown. FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analog approved for MS therapy that can functionally antagonize S1P₁. Here, we report that FTY720 suppresses neuroinflammation by functionally and physically regulating the B₁₂ pathways. Genetic and pharmacological S1P₁ inhibition upregulates a transcobalamin 2 (TCN2)-B₁₂ receptor, CD320, in immediate-early astrocytes (ieAstrocytes; a c-Fos-activated astrocyte subset that tracks with experimental autoimmune encephalomyelitis [EAE] severity). CD320 is also reduced in MS plaques. Deficiency of CD320 or dietary B₁₂ restriction worsens EAE and eliminates FTY720's efficacy while concomitantly downregulating type I interferon signaling. TCN2 functions as a chaperone for FTY720 and sphingosine, whose complex induces astrocytic CD320 internalization, suggesting a delivery mechanism of FTY720/sphingosine via the TCN2-CD320 pathway. Taken together, the B₁₂-TCN2-CD320 pathway is essential for the mechanism of action of FTY720.

Keywords: CP: Neuroscience; cobalamin; demyelination; inflammation; lysophospholipid receptor; neurology; ozanimod; ponesimod; siponimod; sphingolipid; sphingosine kinase.