title: Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network.
abstract: Sphingosine-1-phosphate (S1P), a ligand for 5 specific receptors, is a potent lipid mediator that plays important roles in lymphocyte trafficking and immune responses. S1P is produced inside cells and therefore must be secreted to exert its effects through these receptors. Spinster 2 (Spns2) is one of the cell surface transporters thought to secrete S1P. We have shown that Spns2 can export endogenous S1P from cells and also dihydro-S1P, which is active at all cell surface S1P receptors. Moreover, Spns2 mice have decreased levels of both of these phosphorylated sphingoid bases in blood, accompanied by increases in very long chain ceramide species, and have defective lymphocyte trafficking. Surprisingly, levels of S1P and dihydro-S1P were increased in lymph from Spns2 mice as well as in specific tissues, including lymph nodes, and interstitial fluid. Moreover, lymph nodes from Spns2 mice have aberrant lymphatic sinus that appeared collapsed, with reduced numbers of lymphocytes. Our data suggest that Spns2 is an S1P transporter in vivo that plays a role in regulation not only of blood S1P but also lymph node and lymph S1P levels and consequently influences lymphocyte trafficking and lymphatic vessel network organization.
authors.affiliation: Department of Biochemistry and Molecular Biology, VCU School of Medicine, 1101 E. Marshall St., 2011 Sanger Hall, Richmond, VA 23298, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagahashi
authors.forename: Eugene Y
authors.initials: EY
authors.lastname: Kim
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Yamada
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Allegood
authors.forename: Nitai C
authors.initials: NC
authors.lastname: Hait
authors.forename: Michael
authors.initials: M
authors.lastname: Maceyka
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takabe
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism*; D042601:Lymphatic Vessels / Q000166:cytology / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; D008246:Lysophospholipids; C572630:Spns2 protein, mouse; C060506:sphingosine 1-phosphate; D013110:Sphingosine