title: S1P lyase in thymic perivascular spaces promotes egress of mature thymocytes via up-regulation of S1P receptor 1.
abstract: Sphingosine 1-phosphate (S1P) and S1P receptor 1 (S1P1) play an important role in the egress of mature CD4 or CD8 single-positive (SP) thymocytes from the thymus. Fingolimod hydrochloride (FTY720), an S1P1 functional antagonist, induced significant accumulation of CD62L(high)CD69(low) mature SP thymocytes in the thymic medulla. Immunohistochemical staining using anti-S1P1 antibody revealed that S1P1 is predominantly expressed on thymocytes in the thymic medulla and is strongly down-regulated even at 3h after FTY720 administration. 2-Acetyl-4-tetrahydroxybutylimidazole (THI), an S1P lyase inhibitor, also induced accumulation of mature SP thymocytes in the thymic medulla with an enlargement of the perivascular spaces (PVS). At 6h after THI administration, S1P1-expressing thymocytes reduced partially as if to form clusters and hardly existed in the proximity of CD31-expressing blood vessels in the thymic medulla, suggesting S1P lyase expression in the cells constructing thymic medullary PVS. To determine the cells expressing S1P lyase in the thymus, we newly established a mAb (YK19-2) specific for mouse S1P lyase. Immunohistochemical staining with YK19-2 revealed that S1P lyase is predominantly expressed in non-lymphoid thymic stromal cells in the thymic medulla. In the thymic medullary PVS, S1P lyase was expressed in ER-TR7-positive cells (reticular fibroblasts and pericytes) and CD31-positive vascular endothelial cells. Our findings suggest that S1P lyase expressed in the thymic medullary PVS keeps the tissue S1P concentration low around the vessels and promotes thymic egress via up-regulation of S1P1.
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maeda
authors.forename: Hideki
authors.initials: H
authors.lastname: Yagi
authors.forename: Kana
authors.initials: K
authors.lastname: Takemoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Utsumi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukunari
authors.forename: Kunio
authors.initials: K
authors.lastname: Sugahara
authors.forename: Takashi
authors.initials: T
authors.lastname: Masuko
authors.forename: Kenji
authors.initials: K
authors.lastname: Chiba
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D000068876:Fingolimod Hydrochloride; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D019041:L-Selectin / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology; D011916:Rats, Inbred F344; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D060168:Thymocytes / Q000378:metabolism*; D013950:Thymus Gland / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D000099192:CD69 Antigens
chemical_list: D000446:Aldehyde-Lyases; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000068876:Fingolimod Hydrochloride; D007093:Imidazoles; D019041:L-Selectin; D037181:Lectins, C-Type; D008246:Lysophospholipids; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099192:CD69 Antigens; C060506:sphingosine 1-phosphate; C049929:2-acetyl-4(5)-tetrahydroxybutylimidazole; C022649:sphingosine 1-phosphate lyase (aldolase)
keywords: S1P lyase; S1P1; perivascular spaces; thymic egress; thymus