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

• Published in: Cell reports (Cambridge) Vol. 42; no. 12; p. 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: Journal Article
• Language: English
• Published: United States 26.12.2023
• Subjects: Animals; Astrocytes - metabolism; Encephalomyelitis, Autoimmune, Experimental; Fingolimod Hydrochloride - metabolism; Fingolimod Hydrochloride - pharmacology; Fingolimod Hydrochloride - therapeutic use; Immunosuppressive Agents - pharmacology; Multiple Sclerosis; Propylene Glycols - metabolism; Propylene Glycols - pharmacology; Propylene Glycols - therapeutic use; Receptors, Lysosphingolipid - metabolism; Sphingosine - metabolism; Transcobalamins - metabolism; Transcobalamins - therapeutic use; Vitamin B 12 - metabolism; Vitamin B 12 - pharmacology; Vitamin B 12 - therapeutic use; Vitamins; ozanimod; cobalamin; CP: Neuroscience; inflammation; sphingolipid; demyelination; sphingosine kinase; ponesimod; lysophospholipid receptor; neurology; siponimod
• ISSN: 2211-1247

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.