Vitamin B (B) 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 S1P. Here, we report that FTY720 suppresses neuroinflammation by functionally and physically regulating the B pathways. Genetic and pharmacological S1P inhibition upregulates a transcobalamin 2 (TCN2)-B 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 B 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 B-TCN2-CD320 pathway is essential for the mechanism of action of FTY720.
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| http://dx.doi.org/10.1016/j.celrep.2023.113545 | DOI Listing |
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