title: Lysophosphatidic acid receptors LPA4 and LPA6 differentially promote lymphocyte transmigration across high endothelial venules in lymph nodes.
abstract: Naive lymphocytes continuously migrate from the blood into lymph nodes (LNs) via high endothelial venules (HEVs). To extravasate from the HEVs, lymphocytes undergo multiple adhesion steps, including tethering, rolling, firm adhesion and transmigration. We previously showed that autotaxin (ATX), an enzyme that generates lysophosphatidic acid (LPA), is highly expressed in HEVs, and that the ATX/LPA axis plays an important role in the lymphocyte transmigration across HEVs. However, the detailed mechanism underlying this axis's involvement in lymphocyte transmigration has remained ill-defined. Here, we show that two LPA receptors, LPA4 and LPA6, are selectively expressed on HEV endothelial cells (ECs) and that LPA4 plays a major role in the lymphocyte transmigration across HEVs in mice. In the absence of LPA4 expression, lymphocytes accumulated heavily within the HEV EC layer, compared to wild-type (WT) mice. This accumulation was also observed in the absence of LPA6 expression, but it was less pronounced. Adoptive transfer experiments using WT lymphocytes revealed that the LPA4 deficiency in ECs specifically compromised the lymphocyte transmigration process, whereas the effect of LPA6 deficiency was not significant. These results indicate that the signals evoked in HEV ECs via the LPA4 and LPA6 differentially regulate lymphocyte extravasation from HEVs in the peripheral LNs.
authors.affiliation: Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Hata
authors.affiliation: Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Sasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Takeda
authors.affiliation: Department of Anatomy, Kansai University of Health Sciences, Kumatori, Osaka 590-0482, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tohya
authors.affiliation: Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Umemoto
authors.affiliation: Department of Immunology, Graduate School of Medicine, Akita University, Akita 010-8543, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Akahoshi
authors.affiliation: Department of Immunology, Graduate School of Medicine, Akita University, Akita 010-8543, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishii
authors.affiliation: Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan Genetic Engineering Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Bando
authors.affiliation: Genetic Engineering Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Kuniyuki
authors.initials: K
authors.lastname: Kano
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.affiliation: Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan Department of Life Science, Faculty of Science & Engineering, Kinki University, Higashi-Osaka-shi, Osaka 577-8502, Japan.
authors.forename: Haruko
authors.initials: H
authors.lastname: Hayasaka
authors.affiliation: Interdisciplinary Program for Biomedical Sciences, Institute for Academic Initiatives, Osaka University, Suita, Osaka 565-0871, Japan mmiyasak@orgctl.med.osaka-u.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyasaka
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology*; D008214:Lymphocytes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism*; D011983:Receptors, Purinergic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D057705:Transendothelial and Transepithelial Migration; D000099189:Lysophospholipase D
chemical_list: D010727:Phosphoric Diester Hydrolases; D049368:Receptors, Lysophosphatidic Acid; D011983:Receptors, Purinergic; D000099189:Lysophospholipase D; C523574:Lpar4 protein, mouse
keywords: endothelial cell; high endothelial venule; lymph node; lymphocyte transmigration; lysophosphatidic acid