title: A sphingosine-1-phosphate receptor 1-directed agonist reduces central nervous system inflammation in a plasmacytoid dendritic cell-dependent manner.
abstract: Gradients of the sphingolipid sphingosine-1-phosphate (S1P) are responsible for the egress of lymphocytes from lymph nodes by activating the S1P1 receptor expressed on the surface of lymphocytes. Small molecule drugs that downregulate S1P receptors induce the sequestration of lymphocytes within lymph nodes, thus preventing lymphocytes from accessing sites of inflammation. In particular, FTY720, a pan-S1P receptor agonist, has been efficacious in the treatment of multiple sclerosis as well as its animal model, experimental autoimmune encephalomyelitis (EAE), by virtue of its ability to restrain lymphocytes within the lymph nodes, thus precluding their migration into the CNS. However, multiple leukocyte subsets express S1P receptors of varying types, and although it is beneficial to prevent transmigration of proinflammatory lymphocytes into the CNS, allowing access of regulatory leukocyte subsets to the CNS is desirable. In this study, we show that an S1P1-specific agonist (AUY954) is clinically efficacious in ameliorating pre-established EAE in SJL/J mice. Efficacy of AUY954 correlated with a reduction of lymphocytes in the CNS, but access of plasmacytoid dendritic cells (pDCs) to the CNS was unimpaired, and the presence of pDCs was found to be an important cofactor in mediating the clinical efficacy of AUY954. These results indicate that pDCs are important in quieting autoimmune responses during EAE, and that trafficking inhibitors that are permissive for pDC accumulation in the CNS may be of therapeutic value for the treatment of multiple sclerosis.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Georgina
authors.initials: G
authors.lastname: Galicia-Rosas
authors.forename: Natalia
authors.initials: N
authors.lastname: Pikor
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Schwartz
authors.forename: Olga
authors.initials: O
authors.lastname: Rojas
authors.forename: Allen
authors.initials: A
authors.lastname: Jian
authors.forename: Leslie
authors.initials: L
authors.lastname: Summers-Deluca
authors.forename: Mario
authors.initials: M
authors.lastname: Ostrowski
authors.forename: Barbara
authors.initials: B
authors.lastname: Nuesslein-Hildesheim
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Gommerman
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002449:Cell Aggregation / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D051379:Mice; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism* / Q000502:physiology; D000081025:Sphingosine-1-Phosphate Receptors; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C517408:AUY 954; D000894:Anti-Inflammatory Agents, Non-Steroidal; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D013876:Thiophenes; D015091:beta-Alanine