Protective roles of BLT2 receptor in epithelial barrier function

• Project/Area Number: 15K08316
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Juntendo University
• Principal Investigator: Saeki Kazuko 順天堂大学, 医学部, 准教授 (00553273)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 上皮細胞 / バリア機能 / 生理活性脂質 / 細胞間接着 / 細胞死 / 毒素 / Gタンパク質共役型受容体

Outline of Final Research Achievements

To investigate the roles of BLT2 in epithelial barrier function, we used atopic dermatitis model and acute lung injury model.
Atopic dermatitis model: BLT2-deficient mice exhibited higher transepidermal water loss and were more sensitive to epicutaneous sensitization. Our data using BLT2-overexpressing cells and primary keratinocytes showed that 12-HHT/BLT2 enhances epithelial barrier function by increasing CLDN4 expression via the Gαi protein-p38 MAPK pathway. Acute lung injury model: Intratracheal injection of PLY caused lethal acute lung injury in BLT2-deficient mice, with evident vascular leakage and bronchoconstriction. Large amounts of cysteinyl leukotrienes were detected in PLY-treated lungs. PLY-dependent vascular leakage, bronchoconstriction, and death were markedly ameliorated by treatment with a CysLT1 antagonist. Treatment of mice with NSAIDs inhibited the production of 12-HHT and increased the sensitivity toward PLY, which was also ameliorated by the CysLT1 antagonist.

Academic Significance and Societal Importance of the Research Achievements

非ステロイド性抗炎症薬（NSAIDs）は世界中で広く使用されているものの、効能や副作用の発現メカニズムについては不明な点が多い。NSAIDsがシクロオキシゲナーゼ（COX）を阻害することで多数の生理活性脂質の産生が同時に抑制される為である。本研究において、BLT2欠損マウスで観察されたPLY依存性の個体死が、野性型マウスへのNSAIDs投与でも観察されたことから、NSAIDsが肺炎致死の増悪因子となることを示した。更にこの個体死がCysLT1受容体拮抗薬の前投与で回避できたことから、気管支喘息治療薬として認可されているCysLT1受容体拮抗薬が肺炎球菌による肺炎治療へ応用できる可能性を示した。

Research Products

• [Int'l Joint Research] Shanghai Jiao Tong Univ Sch of Med(中国)
• [Int'l Joint Research] Shahid Beheshti Univ of Med Sciences(イラン)
• [Int'l Joint Research] Harvard Medical School(米国)
• [Int'l Joint Research] IMBA(オーストリア)
• [Int'l Joint Research] 上海交通大学医学院(中国)
• [Int'l Joint Research] Georgia State University(米国)
• [Journal Article] Dietary omega-3 fatty acids alter the lipid mediator profile and alleviate allergic conjunctivitis without modulating Th2 immune responses. (2019)
  • Author(s): Hirakata T., Lee H. C., Ohba M., Saeki K., Okuno T., Murakami A., Matsuda A., Yokomizo T.
  • Journal Title: FASEB J Volume: 33 Issue: 3 Pages: 3392-3403
  • DOI: 10.1096/fj.201801805r
  • Peer Reviewed / Open Access
• [Journal Article] Leukotriene B4 receptor 2 regulates the proliferation migration and barrier integrity of bronchial epithelial cells (2018)
  • Author(s): M Liu J Shen H Yuan F Chen H Song H Qin Y Li J Xu Q Ye S Li K Saeki T Yokomizo
  • Journal Title: J Cell Physiol Volume: 印刷中 Issue: 8 Pages: 6117-6124
  • DOI: 10.1002/jcp.26455
  • 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] 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] 生理活性脂質ロイコトリエン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
  • Journal Title: 臨床免疫・アレルギー科 Volume: 70
• [Journal Article] Biochemical and immunological characterization of a novel monoclonal antibody against mouse leukotriene B4 receptor 1. (2017)
  • Author(s): Sasaki F, Koga T, Saeki K, Okuno T, Kazuno S, Fujimura T, Ohkawa Y, Yokomizo T
  • Journal Title: PLoS One Volume: 12 Issue: 9 Pages: 0185133-0185133
  • DOI: 10.1371/journal.pone.0185133
  • Peer Reviewed / Open Access
• [Journal Article] Identification, signaling, and functions of LTB4 receptors. (2017)
  • Author(s): Saeki K, Yokomizo T
  • Journal Title: Semin Immunol Volume: 33 Pages: 30-36
  • DOI: 10.1016/j.smim.2017.07.010
  • Peer Reviewed / Open Access
• [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] 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] 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] Raftlin Controls Lipopolysaccharide-Induced TLR4 Internalization and TICAM-1 Signaling in a Cell Type-Specific Manner. (2016)
  • Author(s): Tatematsu M, Yoshida R, Morioka Y, Ishii N, Funami K, Watanabe A, Saeki K, Seya T, Matsumoto M
  • Journal Title: J Immunol Volume: 196 Issue: 9 Pages: 3865-3876
  • DOI: 10.4049/jimmunol.1501734
  • Peer Reviewed
• [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
• [Presentation] アレルギー性結膜炎におけるオメガ3脂肪酸の効果の検証 (2018)
  • Author(s): 平形寿彬, 李賢哲, 大塲麻衣, 佐伯和子, 奥野利明, 松田彰, 村上晶, 横溝岳彦
  • Organizer: 第60回日本脂質生化学会
• [Presentation] ロイコトリエンA4水解酵素の代謝における解析 (2018)
  • Author(s): 鵜澤博嗣, 古賀友紹, 奥野利明, 佐伯和子, 横溝岳彦
  • Organizer: 第60回日本脂質生化学会
• [Presentation] 生理活性脂質12-HHTのBLT2受容体を介した生体保護的役割 (2018)
  • Author(s): 佐伯和子, 重松美沙子, 古賀友紹, 奥野利明, 横溝岳彦
  • Organizer: 第91回日本生化学会 シンポジウム
  • Invited
• [Presentation] Protective roles of 12-hydroxyheptadecatrienoic acid/BLT2 in acute lung injury. (2017)
  • Author(s): Shigematsu M, Koga T, Saeki K, Ohba M, Okuno T, Yokomizo T
  • Organizer: Keystone Symposium, Lipidomics and Bioactive Lipids in Metabolism and Disease
  • Place of Presentation: Granlibakken Tahoe (USA)
  • Year and Date: 2017-02-26
  • Int'l Joint Research
• [Presentation] ロイコトリエンB4第一受容体BLT1による免疫活性化機構の解析 (2017)
  • 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: 2017年度生命科学系学会合同年次大会
• [Presentation] ロイコトリエンA4水解酵素の代謝における解析 (2017)
  • Author(s): 鵜澤博嗣, 古賀友紹, 佐伯和子, 宮塚健, 綿田裕孝, 横溝岳彦
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] BLT2のC末端領域はBLT2の細胞間接着部位への局在に重要である (2017)
  • Author(s): 原琢弥, 佐伯和子, 横溝岳彦
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] C-terminal region of BLT2 receptor restricts its localization to the lateral membrane. (2017)
  • Author(s): Hara T, Saeki K, Yokomizo T
  • Organizer: 15th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases
  • Int'l Joint Research
• [Presentation] 12-HHT/BLT2 axis protects against pneumolysin-dependent acute lung injury. (2017)
  • Author(s): Saeki K, Shigematsu M, Koga T, Ohba M, Okuno T, Yokomizo T
  • Organizer: Keystone Symposia Conference, Integrating Metabolism and Immunity
  • Int'l Joint Research
• [Presentation] RAGEはロイコトリエンB4第一受容体BLT1と機能的に相互作用する (2016)
  • Author(s): 市木貴子, 古賀友紹, 奥野利明, 佐伯和子, 阪口政清, 山本靖彦, 横溝岳彦
  • Organizer: 第89回日本生化学会
  • Place of Presentation: 仙台国際センター (仙台)
  • Year and Date: 2016-09-25
• [Presentation] The roles of 12-hydroxyheptadecatrienoic acid/BLT2 axis in skin. (2016)
  • Author(s): Shigematsu M, Koga T, Saeki K, Okuno T, Yokomizo T
  • Organizer: 57th ICBL, International Conference on the Bioscience of Lipids
  • Place of Presentation: Chamonix-Mont-Blanc (France)
  • Year and Date: 2016-09-04
  • Int'l Joint Research
• [Presentation] 12-hydroxyheptadecatrienoic acid (12-HHT) as a novel lipid mediator. (2016)
  • Author(s): Yokomizo T, Ishii Y, Shimegatsu M, Saeki K, Okuno T
  • Organizer: 第58回日本脂質生化学会
  • Place of Presentation: にぎわい交流館AU (秋田)
  • Year and Date: 2016-06-09
  • Invited
• [Presentation] BLT2 receptor protects against lethal acute lung injury induced by a pneumococcal toxin pneumolysin. (2016)
  • Author(s): Shigematsu M, Koga T, Saeki K, Okuno T, Yokomizo T
  • Organizer: ASBMB meeting
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-04-02
  • Int'l Joint Research
• [Presentation] Leukotriene B4 receptor type 2 (BLT2) enhances skin barrier function by regulating tight junction proteins. (2016)
  • Author(s): Ishii Y, Saeki K, Yokomizo T
  • Organizer: ASBMB meeting
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-04-02
  • Int'l Joint Research
• [Presentation] Receptor for advanced glycation endproducts modulates leukotriene B4 receptor 1 signaling. (2016)
  • Author(s): Ichiki T, Koga T, Okuno T, Saeki K, Yamamoto Y, Sakaguchi M, Yokomizo T
  • Organizer: ASBMB meeting
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-04-02
  • Int'l Joint Research
• [Presentation] Roles of leukotriene B4 receptor type 2 in skin barrier function and wound healing. (2016)
  • Author(s): Ishii Y, Liu M, Saeki K, Kabashima K, Yokomizo T
  • Organizer: Keystone Symposium, Immunity in Skin Development, Homeostasis and Disease
  • Place of Presentation: Tahoe(USA)
  • Year and Date: 2016-02-28
  • Int'l Joint Research
• [Presentation] 上皮バリア機能維持における12-HHT受容体BLT2の役割 (2015)
  • Author(s): 佐伯 和子, 石井 由美子, 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 合同大会ワークショップ
  • Place of Presentation: 神戸ポートアイランド（兵庫県・神戸）
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] ロイコトリエンB4第二受容体BLT2は急性肺傷害時に肺保護作用を発揮する (2015)
  • Author(s): 重松美沙子, 古賀友紹, 佐伯和子, 奥野利明, 外須美夫, 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: 神戸ポートアイランド（兵庫県・神戸）
  • Year and Date: 2015-12-01
• [Presentation] ロイコトリエンB4第一受容体(BLT1)とFLAGタグに対するマウス単クローン抗体のヒトキメラ化 (2015)
  • Author(s): 池田恒基, 佐々木文之, 上野あゆみ, 佐伯和子, 奥野利明, 古賀友紹, 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: 神戸ポートアイランド（兵庫県・神戸）
  • Year and Date: 2015-12-01
• [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, 多田 昇, 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: 神戸ポートアイランド（兵庫県・神戸）
  • Year and Date: 2015-12-01
• [Presentation] ロイコトリエンB4第一受容体BLT1とRAGEは機能的に相互作用する (2015)
  • Author(s): 市木貴子, 古賀友紹, 奥野利明, 佐伯和子, 阪口政清, 山本靖彦, 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: 神戸ポートアイランド（兵庫県・神戸）
  • Year and Date: 2015-12-01
• [Presentation] Pneumolysin誘導性急性肺傷害におけるBLT2の肺保護作用 (2015)
  • Author(s): 重松美沙子, 古賀友紹, 佐伯和子, 奥野利明, 横溝岳彦
  • Organizer: 第12回東京呼吸器リサーチフォーラム
  • Place of Presentation: 霞が関コモンゲート（東京・千代田区）
  • Year and Date: 2015-11-14
• [Presentation] BLT2 protects against mouse acute lung injury caused by a pneumococcal toxin pneumolysin. (2015)
  • Author(s): Shigematsu M, Koga T, Saeki K, Okuno T, Hoka S, Yokomizo T
  • Organizer: 14th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases
  • Place of Presentation: Budapest（Hungary）
  • Year and Date: 2015-07-12
  • Int'l Joint Research
• [Presentation] Crucial role of the 12-HHT receptor BLT2 in epidermal wound healing. (2015)
  • Author(s): Liu M, Saeki K, Okuno T, Koga T, Yokomizo T
  • Organizer: 14th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases, Santosh Nigam Memorial Young Scientist Award
  • Place of Presentation: Budapest（Hungary）
  • Year and Date: 2015-07-12
  • Int'l Joint Research
• [Presentation] Platelet-derived lipid mediator, 12-HHT promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor. (2015)
  • Author(s): Saeki K, Liu M, Yokomizo T
  • Organizer: The 37th Congress of the Japanese Society on Thrombosis and Hemostasis
  • Place of Presentation: 甲府市総合市民会館（山梨県・甲府市）
  • Year and Date: 2015-05-21
  • Invited
• [Book] 日本血栓止血学会誌（血小板由来の脂質メディエーター12-HHTは角化細胞の移動を亢進させ皮膚創傷治癒を促進する） (2015)
  • Author(s): 佐伯和子, 劉珉, 横溝岳彦
  • Total Pages: 715
  • Publisher: 日本血栓止血学会
• [Remarks] http://plaza.umin.ac.jp/j_bio/index.html
• [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/index.html
• [Remarks] 順天堂大学医学部生化学第一講座ホームページ
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• [Remarks] 順天堂大学医学部 生化学第一講座
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