Biochemical elucidation of LTA4 hydrolase in immune cells

• Project/Area Number: 17K08664
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Kumamoto University
• Principal Investigator: KOGA TOMOAKI 熊本大学, 発生医学研究所, 助教 (30615092)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: LTA4水解酵素 / 脂質メディエーター / GPCR / ロイコトリエンB4 / 炎症 / 肥満 / 生理活性脂質 / 樹状細胞 / 免疫細胞 / 脂質免疫学 / 脂質エピゲノム / 炎症反応

Outline of Final Research Achievements

Leukotriene B4 (LTB4) is produced from arachidonic acid by leukotriene A4 hydrolase (LTA4H). LTA4H adds water molecule on LTA4 to generate LTB4 and also degrades proteins by using its aminopeptidase activity. LTA4H thus uses lipid and protein as substrates. In the present study, I generated LTA4H knockout mice and analyzed the biological significance of LTA4H in vivo. I found that contact dermatitis was ameliorated and obesity was improved in LTA4H deficient mice. The former is dependent on the LTB4 producing activity of LTA4H, but the latter is independent on the activity. In addition, I identified novel lipid mediator namely RvEx produced by LTA4H.These results suggested the biological significance of LTA4H in inflammation and obesity.

Academic Significance and Societal Importance of the Research Achievements

本研究ではCRISPR/Cas9システムを用いてLTA4H遺伝子欠損マウスを世界で初めて樹立した。また、LTB4産生酵素として知られるLTA4Hであるが、LTB4産生に関わる酵素に比べてかなり広範に発現する理由に関しては長年の謎であった。今回見出した接触性皮膚炎の表現型に関してはLTB4受容体BLT1の遺伝子欠損マウスで矛盾しない結果が得られるため、LTB4依存的であると考えられたが、肥満の表現型はBLT1遺伝子欠損マウスでは見られないため、LTB4非依存的であると考えられた。この発見は学術的に興味深いだけでなく、抗肥満薬の標的としてLTA4Hを提起した重要な知見であった。

Research Products

• [Journal Article] Leukotriene B4 receptor 1 exacerbates inflammation following myocardial infarction. (2020)
  • Author(s): Horii Y, Nakaya M, Ohara H, Nishihara H, Watari K, Nagasaka A, Nakaya T, Sugiura Y, Okuno T, Koga T, Tanaka A, Yokomizo T, Kurose H.
  • Journal Title: FASEB Journal Volume: 印刷中 Issue: 6 Pages: 8749-8763
  • DOI: 10.1096/fj.202000041r
  • Peer Reviewed / Open Access
• [Journal Article] Computational analysis of morphological and molecular features in gastric cancer tissues. (2020)
  • Author(s): Yasuda Y, Tokunaga K, Koga T, Goldberg I, Sakamoto C, *Saitoh N, *Nakao M
  • Journal Title: Cancer Med Volume: 9 Issue: 6 Pages: 2223-2234
  • DOI: 10.1002/cam4.2885
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] α1-acid glycoprotein attenuates adriamycin-induced nephropathy via CD163 expressing macrophages induction (2020)
  • Author(s): Fujimura Rui、Watanabe Hiroshi、Nishida Kento、Fujiwara Yukio、Koga Tomoaki、Bi Jing、Imafuku Tadashi、Kobayashi Kazuki、Komori Hisakazu、Miyahisa Masako、Maeda Hitoshi、Tanaka Motoko、Matsushita Kazutaka、Wada Takashi、Fukagawa Masafumi、Maruyama Toru
  • Journal Title: Kidney360 Volume: ー Issue: 5 Pages: 343-353
  • DOI: 10.34067/kid.0000782019
  • Peer Reviewed / Open Access
• [Journal Article] BLT1 mediates commensal bacteria-dependent innate immune signals to enhance antigen-specific intestinal IgA responses. (2019)
  • Author(s): Nagatake T, Hirata SI, Koga T, Kuroda E, Suzuki H, Hosomi K, Matsumoto N, Yanrismet Y, Shimojou M, Morimoto S, Sasaki F, Ishii KJ, Yokomizo T, Kunisawa J.
  • Journal Title: Mucosal Immunology Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models. (2018)
  • Author(s): Sasaki F., Koga T., Ohba M., Saeki K., Okuno T., Ishikawa K., Nakama T., Nakao S., Yoshida S., Ishibashi T., Ahmadieh H., Kanavi M. R., Hafezi-Moghadam A., Penninger J. M., Sonoda K. H., Yokomizo T.
  • Journal Title: JCI Insight Volume: 3 Issue: 18 Pages: 96902-96902
  • DOI: 10.1172/jci.insight.96902
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Profiling of bioactive lipids in different dendritic cell subsets using an improved multiplex quantitative LC-MS/MS method. (2018)
  • Author(s): Ohba M., Saeki K., Koga T., Okuno T., Kobayashi Y., Yokomizo T.
  • Journal Title: Biochem Biophys Res Commun Volume: 504 Issue: 3 Pages: 562-568
  • DOI: 10.1016/j.bbrc.2018.06.026
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Fusion of Type-I Interferon to a Recombinant Albumin Mutant with polymannosylated N-linked oligosaccharide attached is a Novel and Superior Kupffer Cell Targeting Agent for the Treatment of Hepatitis. (2018)
  • Author(s): Minayoshi Y, Maeda H, Yanagisawa H, Hamasaki K, Mizuta Y, Nishida K, Kinoshita R, Enoki Y, Imafuku T, Chuang VTG, Koga T, Fujiwara Y, Takeya M, Sonoda K, Wakayama T, Taguchi K, Ishima Y, Ishida T, Iwakiri Y, Tanaka M, Sasaki Y, Watanabe H, Otagiri M, Maruyama T.
  • Journal Title: Drug Delivery Volume: 25 Issue: 1 Pages: 1067-1077
  • DOI: 10.1080/10717544.2018.1464083
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of local macrophage growth ameliorates focal inflammation and suppresses atherosclerosis. (2018)
  • Author(s): Yamada S, Senokuchi T, Matsumura T, Morita Y, Ishii N, Fukuda K, Murakami S, Nishida S, Kawasaki S, Motoshima H, Furukawa N, Komohara Y, Fujiwara Y, Koga T, Yamagata K, Takeya M, Araki E
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 印刷中 Issue: 5 Pages: 994-1006
  • DOI: 10.1161/atvbaha.117.310320
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Profiling of bioactive lipids in different dendritic cell subsets using an improved multiplex quantitative LC-MS/MS method (2018)
  • Author(s): Ohba M, Saeki K, Koga T, Okuno T, Kobayashi Y, Yokomizo T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 印刷中
  • Peer Reviewed
• [Presentation] Regulation of Monocytic cell subset by Lipid mediator and Epigenome (2019)
  • Author(s): Tomoaki Koga、Fumiyuki Sasaki、Takehiko Yokomizo、Mitsuyoshi Nakao
  • Organizer: 第42回日本分子生物学会年会 2019年12月5日 福岡
• [Presentation] 炎症・免疫細胞サブセットにおけるエピゲノム因子の機能解析 (2019)
  • Author(s): 古賀友紹、横溝岳彦、中尾光善
  • Organizer: 第43回蛋白質と酵素の構造と機能に関する九州シンポジウム 2019年9月5日～7日 福岡
• [Presentation] 脂質メディエーターとエピゲノムによる単球系サブセットの制御機構 (2019)
  • Author(s): 古賀友紹、横溝岳彦、中尾光善
  • Organizer: 第13回日本エピジェネティクス研究会年会 2019年5月28日～29日 横浜
• [Presentation] 生理活性脂質 LTB4 及びその受容体 BLT1 による 新規樹状細胞サブセット制御機構 (2018)
  • Author(s): 古賀友紹, 佐々木文之, 佐伯和子, 奥野利明, 中尾光善, 横溝岳彦.
  • Organizer: 第15回 東京呼吸器リサーチフォーラム
• [Presentation] ロイコトリエンB4第一受容体により規定される新規樹状細胞サブセットの同定 (2018)
  • Author(s): 古賀友紹、中尾光善、横溝岳彦
  • Organizer: 第12回 日本エピジェネティクス研究会年会
• [Presentation] 生理活性脂質ロイコトリエンB4とその受容体BLT1による生体防御応答 (2017)
  • Author(s): 古賀友紹、中尾光善、横溝岳彦
  • Organizer: 第７回 オルソオルガノジェネシス検討会
  • Invited
• [Presentation] 生理活性脂質ロイコトリエンB4とその受容体BLT1による免疫制御機構の解析 (2017)
  • Author(s): 古賀友紹、中尾光善、横溝岳彦
  • Organizer: 第41回 蛋白質と酵素の構造と機能に関する九州シンポジウム
• [Book] 臨床免疫・アレルギー科 第70巻 ロイコトリエンB4とその受容体による免疫調節機構 (2018)
  • Author(s): 古賀友紹, 佐伯和子, 横溝岳彦.
  • Total Pages: 10
  • Publisher: 科学評論社