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

• Published in: Cell reports (Cambridge) 2023-12, Vol.42 (12), p.113545-113545, Article 113545
• Main Authors: Jonnalagadda, Deepa, Kihara, Yasuyuki, Groves, Aran, Ray, Manisha, Saha, Arjun, Ellington, Clayton, Lee-Okada, Hyeon-Cheol, Furihata, Tomomi, Yokomizo, Takehiko, Quadros, Edward V., Rivera, Richard, Chun, Jerold
• Format: Article
• Language: English
• Subjects: cobalamin; CP: Neuroscience; demyelination; inflammation; lysophospholipid receptor; neurology; ozanimod; ponesimod; siponimod; sphingolipid; sphingosine kinase
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113545

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. [Display omitted] •CD320 expression is suppressed in MS and EAE astrocytes•S1P1 inhibition upregulates CD320 expression in astrocytes•Fingolimod and sphingosine directly bind to TCN2•Fingolimod-bound TCN2 promotes CD320 internalization in astrocytes Jonnalagadda et al. find fingolimod-mediated maintenance of vitamin B12 homeostasis in the CNS. Fingolimod binds directly to TCN2 to form a complex that promotes vitamin B12 availability in astrocytes through internalization of CD320, followed by phosphorylation of fingolimod, which functionally antagonizes S1P1, resulting in upregulation of CD320 in astrocytes.