Elucidation of leukotriene B4 receptor 1, BLT1-dependent immune response by dendritic cells and neutrophils

• Project/Area Number: 15K19032
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Kumamoto University (2016); Juntendo University (2015)
• Principal Investigator: KOGA TOMOAKI 熊本大学, 大学院先導機構, 助教 (30615092)
• Co-Investigator(Renkei-kenkyūsha): Yokomizo Takehiko 順天堂大学, 医学部・生化学第一講座, 教授 (60302840)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 生理活性脂質 / 好中球 / 樹状細胞 / GPCR / ロイコトリエンB4 / BLT1 / リピドミクス / RAGE / LTB4 / LTA4H / コンディショナルノックアウト

Outline of Final Research Achievements

In the present study, we investigated the role of LTB4-BLT1 axis in neutrophils and dendritic cells. We found that BLT1 interacts with receptor for advanced glycation end products (RAGE), which is important receptor for the regulation of various chronic inflammatory diseases including diabetes, atherosclerosis, Alzheimer's diseases and etc. We also showed that RAGE enhances LTB4-BLT1-dependent neutrophil migration in vitro and in vivo through the activation of MEK-ERK signaling pathway. RAGE is known to be up-regulated by aging, so it might be possible that BLT1 signaling is exaggerated by aging through RAGE induction in vivo. If we can inhibit RAGE, we might also inhibit LTB4-BLT1 signaling, and subsequent infiltration of neutrophils into inflammatory area. We therefore propose RAGE as a novel therapeutic target for various inflammatory diseases by targeting LTB4-BLT1 signaling.

Research Products

• [Int'l Joint Research] ジョージア州立大学/生命医科学研究所/リ・ジェンドン所長（教授）(米国)
• [Journal Article] Generation and characterization of a human-mouse chimeric high-affinity antibody that detects the DYKDDDDK FLAG peptide (2017)
  • Author(s): Ikeda K, Koga T, Sasaki F, Ueno A, Saeki K, Okuno T, Yokomizo T.
  • Journal Title: Biochem Biophys Res Commun Volume: 486 Issue: 4 Pages: 1077-1082
  • DOI: 10.1016/j.bbrc.2017.03.165
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mild electrical stimulation with heat shock guides differentiation of embryonic stem cells into Pdx1-expressing cells within the definitive endoderm. (2017)
  • Author(s): Koga T, Shiraki N, Yano S, Suico MA, Morino-Koga S, Sato T, Shuto T, Kume S, Kai H
  • Journal Title: BMC Biotechnology Volume: 17 Issue: 1 Pages: 14-14
  • DOI: 10.1186/s12896-017-0331-z
  • Peer Reviewed / Open Access
• [Journal Article] Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. (2017)
  • Author(s): Loo TM, Kamachi F, Watanabe Y, Yoshimoto S, Kanda H, Arai Y, Nakajima-Takagi Y, Iwama A, Koga T, Sugimoto Y, Ozawa T, Nakamura M, Kumagai M, Watashi K, Taketo M, Aoki T, Narumiya S, Oshima M, Arita M, Hara E, Ohtani N.
  • Journal Title: Cancer Discov Volume: in press Issue: 5 Pages: 522-538
  • DOI: 10.1158/2159-8290.cd-16-0932
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of Leukotriene B4 Action Mitigates Intracerebral Hemorrhage-Associated Pathological Events in Mice (2017)
  • Author(s): Hijioka, M., Anan, J., Ishibashi, H., Kurauchi, Y., Hisatsune, A., Seki, T., Koga, T., Yokomizo, T., Shimizu, T.,Katsuki, H.
  • Journal Title: J Pharmacol Exp Ther Volume: 360 Issue: 3 Pages: 399-408
  • DOI: 10.1124/jpet.116.238824
  • Peer Reviewed
• [Journal Article] An aromatic amino acid within intracellular loop 2 of the prostaglandin EP2 receptor is a prerequisite for selective association and activation of Gαs. (2017)
  • Author(s): Yano A, Takahashi Y, Moriguchi H, Inazumi T, Koga T, Otaka A, Sugimoto Y.
  • Journal Title: Biochim Biophys Acta Mol Cell Biol Lipids Volume: 1862 Issue: 6 Pages: 615-622
  • DOI: 10.1016/j.bbalip.2017.03.006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Receptor for Advanced Glycation End Products Regulates Leukotriene B4 Receptor 1 Signaling (2016)
  • Author(s): Ichiki, T., Koga, T.,Yokomizo, T.
  • Journal Title: DNA Cell Biol Volume: 35 Issue: 12 Pages: 747-750
  • DOI: 10.1089/dna.2016.3552
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Modulation of leukotriene B4 receptor 1 signaling by receptor for advanced glycation end products, RAGE. (2016)
  • Author(s): Ichiki T, Koga T, Okuno T, Saeki K, Yamamoto Y, Yamamoto H, Sakaguchi M, Yokomizo T
  • Journal Title: FASEB J Volume: 30 Issue: 5 Pages: 1811-1822
  • DOI: 10.1096/fj.201500117
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Leukotriene B4 receptor type 2 protects against pneumolysin-dependent acute lung injury (2016)
  • Author(s): Shigematsu, M., Koga, T., Ishimori, A., Saeki, K., Ishii, Y., Taketomi, Y., Ohba, M., Jo-Watanabe, A., Okuno, T., Harada, N., Harayama, T., Shindou, H., Li, J. D., Murakami, M., Hoka, S.,Yokomizo, T.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 34560-34560
  • DOI: 10.1038/srep34560
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Leukotriene B4 receptor type 2 (BLT2) enhances skin barrier function by regulating tight junction proteins. (2016)
  • Author(s): Ishii Y, Saeki K, Liu M, Sasaki F, Koga T, Kitajima K, Meno C, Okuno T, Yokomizo T
  • Journal Title: FASEB J Volume: 30 Issue: 2 Pages: 933-947
  • DOI: 10.1096/fj.15-279653
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Podocyte p53 limits the severity of experimental Alport syndrome. (2015)
  • Author(s): Fukuda R., et al.
  • Journal Title: Jounal of American Society of Nephrology Volume: just accepted Issue: 1 Pages: 144-157
  • DOI: 10.1681/asn.2014111109
  • Peer Reviewed / Open Access
• [Journal Article] Endoplasmic Reticulum (ER) Stress Induces Sirtuin 1 (SIRT1) Expression via the PI3K-Akt-GSK3β Signaling Pathway and Promotes Hepatocellular Injury. (2015)
  • Author(s): Koga T, Suico MA, Shimasaki S, Watanabe E, Kai Y, Koyama K, Omachi K, Morino-Koga S, Sato T, Shuto T, Mori K, Hino S, Nakao M, Kai H.
  • Journal Title: J Biol Chem. Volume: 290 Issue: 51 Pages: 30366-30374
  • DOI: 10.1074/jbc.m115.664169
  • Peer Reviewed / Open Access
• [Presentation] CRISPR/Cas9を用いたLeukotriene A4 hydrolase 欠損マウスの作製 (2016)
  • Author(s): 古賀友紹、奥野利明、佐伯和子、横溝岳彦
  • Organizer: 第40回 タンパク質と酵素の機能に関する九州シンポジウム
  • Place of Presentation: 指宿ベイテラス
  • Year and Date: 2016-08-26
• [Presentation] Expression and Function of Leukotriene B4 receptor 1 in dendritic cells (2016)
  • Author(s): Tomoaki Koga, Fumiyuki Sasaki, Kazuko Saeki, Takako Ichiki, Toshiaki Okuno, Takehiko Yokomizo
  • Organizer: Environment Controlling normal and diseased hematopoietic and immune systems
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-02
• [Presentation] CRISPR/Cas9によるロイコトリエンA4水解酵素欠損マウスの作製 (2015)
  • Author(s): 古賀友紹, 奥野利明, 佐伯和子, 中村衣里, 多田昇弘, 横溝岳彦
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Book] 医学のあゆみ256巻5号 GPCR研究の最前線2016「ロイコトリエン受容体」 (2016)
  • Author(s): 市木貴子, 古賀友紹, 横溝岳彦
  • Total Pages: 10
  • Publisher: 医歯薬出版
• [Book] Leukotriene B4 Receptors. In “Bioactive Lipid Mediators: Current Reviews and Protocols” (Murakami M, Yokomizo T, Ed) (2015)
  • Author(s): Koga T, Yokomizo T
  • Total Pages: 9
  • Publisher: Springer (Tokyo)
• [Book] 「疾患モデルの作製と利用―脂質代謝異常と関連疾患」下巻 第5章 脂質メディエーター、第4節 ロイコトリエン (2015)
  • Author(s): 古賀友紹, 横溝岳彦
  • Total Pages: 9
  • Publisher: エルアイシー出版
• [Remarks] 順天堂大学医学部生化学第一講座ホームページ
  • URL: http://plaza.umin.ac.jp/j_bio/Biochem1/Top.html