| First Author | Jonnalagadda D | Year | 2023 |
| Journal | Cell Rep | Volume | 42 |
| Issue | 12 | Pages | 113545 |
| PubMed ID | 38064339 | Mgi Jnum | J:347963 |
| Mgi Id | MGI:7570038 | Doi | 10.1016/j.celrep.2023.113545 |
| Citation | Jonnalagadda D, et al. (2023) FTY720 requires vitamin B(12)-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis. Cell Rep 42(12):113545 |
| abstractText | Vitamin B(12) (B(12)) 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(1). Here, we report that FTY720 suppresses neuroinflammation by functionally and physically regulating the B(12) pathways. Genetic and pharmacological S1P(1) inhibition upregulates a transcobalamin 2 (TCN2)-B(12) 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(12) 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(12)-TCN2-CD320 pathway is essential for the mechanism of action of FTY720. |
