FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis
Deepa Jonnalagadda,
Yasuyuki Kihara,
Aran Groves,
Manisha Ray,
Arjun Saha,
Clayton Ellington,
Hyeon-Cheol Lee-Okada,
Tomomi Furihata,
Takehiko Yokomizo,
Edward V. Quadros,
Richard Rivera,
Jerold Chun
Affiliations
Deepa Jonnalagadda
Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA
Yasuyuki Kihara
Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA; Corresponding author
Aran Groves
Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA; Neuroscience Graduate Program, School of Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
Manisha Ray
Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA
Arjun Saha
Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA
Clayton Ellington
Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA
Hyeon-Cheol Lee-Okada
Department of Biochemistry, Graduate School of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan
Tomomi Furihata
Laboratory of Clinical Pharmacy and Experimental Therapeutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
Takehiko Yokomizo
Department of Biochemistry, Graduate School of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan
Edward V. Quadros
Department of Medicine, SUNY-Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
Richard Rivera
Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA
Jerold Chun
Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA; Corresponding author
Summary: 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.
