title: Sphingosine-1-phosphate receptor-1 (S1P1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease.
abstract: The sphingosine-1-phosphate receptor-1 (S1P1) agonist ozanimod ameliorates ulcerative colitis, yet its mechanism of action is unknown. Here, we examine the cell subsets that express S1P1in intestine using S1P1-eGFP mice, the regulation of S1P1expression in lymphocytes after administration of dextran sulfate sodium (DSS), after colitis induced by transfer of CD4+CD45RBhicells, and by crossing a mouse with TNF-driven ileitis with S1P1-eGFP mice. We then assayed the expression of enzymes that regulate intestinal S1P levels, and the effect of FTY720 on lymphocyte behavior and S1P1expression. We found that not only T and B cells express S1P1, but also dendritic (DC) and endothelial cells. Furthermore, chronic but not acute inflammatory signals increased S1P1expression, while the enzymes that control tissue S1P levels in mice and humans with inflammatory bowel disease (IBD) were uniformly dysregulated, favoring synthesis over degradation. Finally, we observed that FTY720 reduced T-cell velocity and induced S1P1degradation and retention of Naïve but not effector T cells. Our data demonstrate that chronic inflammation modulates S1P1expression and tissue S1P levels and suggests that the anti-inflammatory properties of S1PR agonists might not be solely due to their lymphopenic effects, but also due to potential effects on DC migration and vascular barrier function.
authors.affiliation: Division of Gastroenterology, Inflammatory Bowel Disease Center, University of California San Diego, La Jolla, California, USA.|VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: T
authors.initials: T
authors.lastname: Karuppuchamy
authors.affiliation: Division of Gastroenterology, Inflammatory Bowel Disease Center, University of California San Diego, La Jolla, California, USA.|VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: E-H
authors.initials: EH
authors.lastname: Behrens
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: P
authors.initials: P
authors.lastname: González-Cabrera
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: G
authors.initials: G
authors.lastname: Sarkisyan
authors.affiliation: Division of Gastroenterology, Inflammatory Bowel Disease Center, University of California San Diego, La Jolla, California, USA.|VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: L
authors.initials: L
authors.lastname: Gima
authors.affiliation: Division of Gastroenterology, Inflammatory Bowel Disease Center, University of California San Diego, La Jolla, California, USA.|VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Boyer
authors.affiliation: Academic Department of Gastroenterology, Laikon Hospital, Athens, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Bamias
authors.affiliation: Department of Pathology, University of Colorado Health Sciences, Aurora, Colorado, USA.
authors.forename: P
authors.initials: P
authors.lastname: Jedlicka
authors.affiliation: Division of Gastroenterology, Inflammatory Bowel Disease Center, University of California San Diego, La Jolla, California, USA.|VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Veny
authors.affiliation: Division of Gastroenterology, Inflammatory Bowel Disease Center, University of California San Diego, La Jolla, California, USA.|VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: D
authors.initials: D
authors.lastname: Clark
authors.affiliation: Receptos Inc., La Jolla, California, USA.
authors.forename: R
authors.initials: R
authors.lastname: Peach
authors.affiliation: Receptos Inc., La Jolla, California, USA.
authors.forename: F
authors.initials: F
authors.lastname: Scott
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: H
authors.initials: H
authors.lastname: Rosen
authors.affiliation: Division of Gastroenterology, Inflammatory Bowel Disease Center, University of California San Diego, La Jolla, California, USA.|VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: J
authors.initials: J
authors.lastname: Rivera-Nieves
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004727:Endothelium / Q000276:immunology*; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D007156:Immunologic Memory; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology*; D007422:Intestines / Q000502:physiology*; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010069:Oxadiazoles / Q000494:pharmacology / Q000627:therapeutic use; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D007155:Immunologic Factors; D007189:Indans; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; D016264:Dextran Sulfate; D000068876:Fingolimod Hydrochloride; C000607776:ozanimod