{"doi":"10.1016/j.celrep.2023.113545","title":"FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis","abstract":"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.","journal":"Cell Reports","year":2023,"id":339057,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":584518,"name":"Yasuyuki Kihara","orcid":"0000-0001-7462-3006","position":1,"is_corresponding":false},{"id":990404,"name":"Aran Groves","orcid":null,"position":2,"is_corresponding":false},{"id":584517,"name":"Manisha Ray","orcid":"0000-0001-7145-6601","position":3,"is_corresponding":false},{"id":469003,"name":"Arjun Saha","orcid":"0000-0003-1198-1820","position":4,"is_corresponding":false},{"id":576785,"name":"Clayton Ellington","orcid":null,"position":5,"is_corresponding":false},{"id":990050,"name":"Hyeon‐Cheol Lee","orcid":"0000-0002-5493-8112","position":6,"is_corresponding":false},{"id":990051,"name":"Tomomi Furihata","orcid":"0000-0003-3614-9328","position":7,"is_corresponding":false},{"id":772325,"name":"Takehiko Yokomizo","orcid":"0000-0002-5219-1553","position":8,"is_corresponding":false},{"id":356688,"name":"Edward V. Quadros","orcid":"0000-0002-7663-8014","position":9,"is_corresponding":false},{"id":772321,"name":"Richard Rivera","orcid":"0000-0001-6138-3306","position":10,"is_corresponding":false},{"id":38374,"name":"Jerold Chun","orcid":"0000-0003-3964-0921","position":11,"is_corresponding":false},{"id":772320,"name":"Deepa Jonnalagadda","orcid":"0000-0002-1511-8197","position":0,"is_corresponding":true}],"reference_count":98,"raw_metadata":null,"created_at":"2026-07-19T01:10:45.048445Z","pmid":"38064339","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}