title: FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation.
abstract: Sphingosine 1-phosphate (S1P), a lysophospholipid, has gained relevance to multiple sclerosis through the discovery of FTY720 (fingolimod), recently approved as an oral treatment for relapsing forms of multiple sclerosis. Its mechanism of action is thought to be immunological through an active phosphorylated metabolite, FTY720-P, that resembles S1P and alters lymphocyte trafficking through receptor subtype S1P(1). However, previously reported expression and in vitro studies of S1P receptors suggested that direct CNS effects of FTY720 might theoretically occur through receptor modulation on neurons and glia. To identify CNS cells functionally contributing to FTY720 activity, genetic approaches were combined with cellular and molecular analyses. These studies relied on the functional assessment, based on clinical score, of conditional null mouse mutants lacking S1P(1) in CNS cell lineages and challenged by experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. All conditional null mutants displayed WT lymphocyte trafficking that responded normally to FTY720. In marked contrast, EAE was attenuated and FTY720 efficacy was lost in CNS mutants lacking S1P(1) on GFAP-expressing astrocytes but not on neurons. In situ hybridization studies confirmed that astrocyte loss of S1P(1) was the key alteration in functionally affected mutants. Reductions in EAE clinical scores were paralleled by reductions in demyelination, axonal loss, and astrogliosis. Receptor rescue and pharmacological experiments supported the loss of S1P(1) on astrocytes through functional antagonism by FTY720-P as a primary FTY720 mechanism. These data identify nonimmunological CNS mechanisms of FTY720 efficacy and implicate S1P signaling pathways within the CNS as targets for multiple sclerosis therapies.
authors.affiliation: Department of Molecular Biology, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Ji Woong
authors.initials: JW
authors.lastname: Choi
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Gardell
authors.forename: Deron R
authors.initials: DR
authors.lastname: Herr
authors.forename: Richard
authors.initials: R
authors.lastname: Rivera
authors.forename: Chang-Wook
authors.initials: CW
authors.lastname: Lee
authors.forename: Kyoko
authors.initials: K
authors.lastname: Noguchi
authors.forename: Siew Teng
authors.initials: ST
authors.lastname: Teo
authors.forename: Yun C
authors.initials: YC
authors.lastname: Yung
authors.forename: Melissa
authors.initials: M
authors.lastname: Lu
authors.forename: Grace
authors.initials: G
authors.lastname: Kennedy
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D000068876:Fingolimod Hydrochloride; D005786:Gene Expression Regulation; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000188:drug therapy*; D011409:Propylene Glycols / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D043562:Receptors, G-Protein-Coupled; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine