Regulation of lymphocyte trafficking by the autotaxin/LPA axis

• Project/Area Number: 24590252
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General anatomy (including Histology/Embryology)
• Research Institution: Osaka University
• Principal Investigator: UMEMOTO Eiji 大阪大学, 医学(系)研究科(研究院), 准教授 (90452440)
• Co-Investigator(Renkei-kenkyūsha): SUGIURA Yuki 慶応義塾大学, 医学系研究科, 特任講師 (30590202) ; TOHYA Kazuo 関西医療大学, 保健医療学部, 教授 (90183491) ; MIYASAKA Masayuki 大阪大学, 未来戦略機構, 特任教授 (50064613)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: リゾリン脂質 / リゾホスファチジン酸 / リンパ球トラフィキング / リンパ節 / 繊維芽様細網細胞 / 血管内皮細胞 / 細網繊維芽細胞

Outline of Final Research Achievements

Blood-borne naive lymphocytes continually migrate into lymph nodes (LNs) via specialized venules called high endothelial venules (HEVs). Once entering LNs, they actively migrate along the fibroblastic reticular cell (FRC) network scanning for cognate antigens. However, a cell-extrinsic factor regulating lymphocyte migration remains poorly understood.
Autotaxin (ATX) is a secretory enzyme that produces lysophosphatidic acid (LPA), a bioactive lysophospholipid. In this study, we found that HEV endothelial cells and FRCs selectively express ATX and that ATX's end-product LPA promotes lymphocyte migration across HEVs as well as their interstitial migration in LNs. Thus, the ATX/LPA axis critically regulates multiple processes of lymphocyte migration into/within LNs.

Research Products

• [Journal Article] The ectoenzyme E-NPP3 negatively regulates ATP-dependent chronic allergic responses by basophils and mast cells. (2015)
  • Author(s): Tsai, S-H., Kinoshita, M., Kusu, T., Kayama, H., Okumura, R., Ikeda, K., Shimada, Y., Takeda, A., Yoshikawa, S., Obata-Ninomiya, K., Kurashima, Y., Sato, S., Umemoto, E., Kiyono, H., Karasuyama, H. and Takeda, K.
  • Journal Title: Immunity Volume: 42(2) Pages: 279-293
  • DOI: 10.1016/j.immuni.2015.01.015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The endothelial protein PLVAP in lymphatics controls the entry of lymphocytes and antigens into lymph nodes. (2015)
  • Author(s): Rantakari P, Auvinen K, Jäppinen N, Kapraali M, Valtonen J, Karikoski M, Gerke H, Iftakhar-E-Khuda I, Keuschnigg J, Umemoto E, Tohya K, Miyasaka M, Elima K, Jalkanen S, Salmi M.
  • Journal Title: Nat Immunol. Volume: １６ Pages: 386-396
  • DOI: 10.1038/ni.3101
  • Peer Reviewed / Open Access
• [Journal Article] Toll-like receptor 4 and MAIR-II/CLM-4/LMIR2 immunoreceptor regulate VLA-4-mediated infammatory monocyte migration (2014)
  • Author(s): Naoya T otsuka, Yun-Gi Kim, Kazumasa Kanemaru, Kouta Niizuma, Eiji Umemoto, Kei Nagai, Satoko T ahara-Hanaoka, Chigusa Nakahasi-Oda, Shin-ichiro Honda, Masayuki Miyasaka, Kazuko Shibuya & Akira Shibuya
  • Journal Title: Nat Commun. Volume: 5:4710 Pages: 4710-4710
  • DOI: 10.1038/ncomms5710
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Generation of colonic IgA-secreting cells in the cecal patch (2014)
  • Author(s): Masahata, K., Umemoto, E., Kayama, H., Kotani, M., Nakamura, S., Kurakawa, T., Kikuta, J., Gotoh, K., Motooka, D., Sato, S., Higuchi, T., Baba, Y., Kurosaki, T., Kinoshita, M., Shimada, Y., Kimura, T., Okumura, R., Takeda, A., Tajima, M., Yoshie, O., Fukuzawa, M., Kiyono, H., Fagarasan, S., Iida, T., Ishii, M., Takeda, K
  • Journal Title: Nature Comm. Volume: 5 Pages: 1-13
  • DOI: 10.1038/ncomms4704
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Ifit1 inhibits Japanese encephalitis virus replication through binding to 5' capped 2'-O unmethylated RNA. (2013)
  • Author(s): Kimura T, Katoh H, Kayama H, Saiga H, Okuyama M, Okamoto T, Umemoto E, Matsuura Y, Yamamoto M, Takeda K
  • Journal Title: Journal of Virology Volume: 87 Pages: 9997-10003
  • DOI: 10.1128/jvi.00883-13
  • Peer Reviewed
• [Journal Article] Four-dimensional spatial nanometry of single particles in living cells using polarized quantum rods (2013)
  • Author(s): Watanabe TM, Fujii F, Jin T, Umemoto E, Miyasaka M, Fujita H, Yanagida T.
  • Journal Title: Biophys J. Volume: 105 Pages: 555-564
  • DOI: 10.1016/j.bpj.2013.07.001
  • Peer Reviewed
• [Journal Article] Dynamic changes in endothelial cell adhesion molecule nepmucin/CD300LG expression under physiological and pathological conditions. (2013)
  • Author(s): Umemoto, E, Takeda, A., Jin, S., Luo, Z., Nakahogi, N., Hayasaka, H., Lee, C.M., Tanaka, T. & Miyasaka, M.
  • Journal Title: PLOS One Volume: 8 Pages: 1-12
  • DOI: 10.1371/journal.pone.0083681
  • Peer Reviewed
• [Journal Article] Constitutive lymphocyte transmigration across the basal lamina of high endothelial venules is regulated by the autotaxin/lysophosphatidic acid axis (2013)
  • Author(s): Bai Z
  • Journal Title: J Immunol. Volume: 190 Pages: 2036-2048
  • DOI: 10.4049/jimmunol.1202025
  • Peer Reviewed
• [Presentation] The cecal patch is a major site for generation of colonic IgA-secreting cells. (2014)
  • Author(s): Eiji Umemoto, Kayama Hisako, Junichi Kikuta, Ryu Okumura, Akira Takeda, Masaru Ishii, Kiyoshi Takeda
  • Organizer: 第43回日本免疫学会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] The role of LPA4/6 receptors in lymphocyte trafficking across high endothelial venules of lymph nodes (2014)
  • Author(s): Erina Hata, Naoko Sasaki, Akira Takeda, Eiji Umemoto, Haruko Hayasaka, Masayuki Miyasaka
  • Organizer: 第43回日本免疫学会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Lymphocytes caught before the act - how Spinster-homologue-2 (Spns2) controls S1P-driven lymphocyte egress from lymphoid organs (2014)
  • Author(s): Szandor Simmons, Eiji Umemoto, Shigetomo Fukuhara, Yusuke Kitazawa, Michiyo Okudaira, Asuka Inoue, Shota Nakamura, Tetsuya Iida, Junken Aoki, Kenjiro Matsuno, Masayuki Miyasaka, Kiyoshi Takeda, Masaru Ishii
  • Organizer: 第43回日本免疫学会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Lypd8 mainteins gut homeostasis by preventing pathobiont attachment to the colonic epithelia (2014)
  • Author(s): Ryu Okumura, Eiji Umemoto, Hisako Kayama, Makoto Kinoshita, Kiyoshi Takeda
  • Organizer: 第43回日本免疫学会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] 脾臓におけるケモカインの発現と白血球動態 (2014)
  • Author(s): 梅本英司・宮坂昌之
  • Organizer: 日本解剖学会
  • Place of Presentation: 栃木
  • Invited
• [Presentation] オートタシキン/リゾホスファチジン酸はリンパ節高内皮細静脈の基底膜におけるリンパ球の通過を制御する (2013)
  • Author(s): 梅本英司・宮坂昌之
  • Organizer: 日本リンパ学会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] The role of LPA receptors on lymphocytes in lymphocyte trafficking across high endothelial venules of lymph nodes (2013)
  • Author(s): Akira Takeda, Eiji Umemoto, Erina Hata, Naoko Sasaki, and Masayuki Miyasaka
  • Organizer: 日本免疫学会
  • Place of Presentation: 千葉
• [Presentation] The role of LPA receptors on endothelial cells in lymphocyte trafficking across high endothelial venules of lymph nodes (2013)
  • Author(s): Erina Hata, Naoko Sasaki, Akira Takeda, Eiji umemoto, Haruko Hayasaka, and Masayuki Miyasaka
  • Organizer: 日本免疫学会
  • Place of Presentation: 千葉
• [Presentation] オートタキシン/リゾホスファチジン酸は、リンパ節高内皮細静脈の基底膜におけるリンパ球の通過を制御する (2013)
  • Author(s): 梅本英司
  • Organizer: 第37回日本リンパ学会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] Autotaxin-derived lysophosphatidic acid acts on high endothelial venule endothelial cells to promote lymphocyte-endothelial cell interactions. (2012)
  • Author(s): Takeda A, Umemoto E, Hata E, and Miyasaka M.
  • Organizer: 第41回日本免疫学会
  • Place of Presentation: 神戸