Elucidation of the host's homeostatic responses by the regulation of immune system and its application to the prevention and treatment of immunological disorders

2019 Fiscal Year Annual Research Report

• Project/Area Number: 15H05787
• Research Institution: The University of Tokyo
• Principal Investigator: 谷口 維紹 東京大学, 先端科学技術研究センター, 名誉教授 (50133616)
• Co-Investigator(Kenkyū-buntansha): 岩倉 洋一郎 東京理科大学, 研究推進機構生命医科学研究所, 教授 (10089120) ; 西尾 純子 東京大学, 先端科学技術研究センター, 特任助教 (40598679) [Withdrawn] ; 藤尾 圭志 東京大学, 医学部附属病院, 教授 (70401114) ; 柳井 秀元 東京大学, 先端科学技術研究センター, 特任准教授 (70431765)
• Project Period (FY): 2015-05-29 – 2020-03-31
• Keywords: 免疫シグナル伝達 / 恒常性維持 / 自然免疫受容体 / HMGB1 / がん / 炎症 / 自己免疫疾患 / 免疫原性核酸

Outline of Annual Research Achievements

本研究は、自然免疫系を基軸として適応免疫系をも視野に入れ、生体の恒常性維持のメカニズムを解明し、その変容や破綻がもたらす各種疾患の予防・治療法に向けた分子基盤を確立することを目的としている。特に、自己由来免疫制御分子、及び、独自に取得した免疫系を干渉する低分子化合物、の二方面からの研究を推進している。本年度において、DAMPsとして知られているHMGB1について解析を行い、HMGB1が炎症時の好中球を遊走させるメカニズムについて解析を進めた。またさらに、炎症を促進させる新規DAMPs の探索を行い、候補分子について解析を行なった。がんの免疫微小環境を制御し、がんの増大に関与するDAMPが存在することが判明し、その詳細な機能解析を行なった。
また、高い免疫原性を有するRNAについて解析を進め、U11snRNAを同定した。U11snRNAはこれまで知られていた自己に由来するRNAと比較し、RNA受容体に対する強いリガンド活性を有することが判明した。また、U11snRNAの強いリガンド活性のメカニズムを解明し、その原理を元に、RNA受容体を強力に活性化するアゴニスト、および抑制アンタゴニストの作成にもそれぞれ成功した。本成果から、RNAを認識する自然免疫受容体が関与する種々の疾患の発症や増悪のメカニズム解明に繋がることが期待される。また、KN69やアンタゴニストは疾患の治療薬として、アゴニストは感染症やがんに対するワクチンの効果を高めるアジュバントとして有用である可能性が示唆された。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] IFN-γ and IL-17A regulate intestinal crypt production of CXCL10 in the healthy and inflamed colon (2020)
  • Author(s): Walrath Travis、Malizia Robert A.、Zhu Xinjun、Sharp Stephen P.、D'Souza Shanti S.、Lopez-Soler Reynold、Parr Brian、Kartchner Brittany、Lee Edward C.、Stain Steven C.、Iwakura Yoichiro、O'Connor William
  • Journal Title: American Journal of Physiology-Gastrointestinal and Liver Physiology Volume: 318 Pages: G479～G489
  • DOI: 10.1152/ajpgi.00208.2019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IL-17A promotes fatty acid uptake through the IL-17A/IL-17RA/p-STAT3/FABP4 axis to fuel ovarian cancer growth in an adipocyte-rich microenvironment (2020)
  • Author(s): Chunyan Yu、 Xiulong Niu、 Yongrui Du、 Yan Chen、 Xiaomei Liu、 Lingling Xu、 Yoichiro Iwakura、 Xiaoxia Ma、 Yan Li、 Zhi Yao & Weimin Deng
  • Journal Title: Cancer Immunol Immunother Volume: 69 Pages: 115-126
  • DOI: 10.1007/s00262-019-02445-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Interleukin 17A: a Janus-faced regulator of osteoporosis (2020)
  • Author(s): Scheffler J. M.、Grahnemo L.、Engdahl C.、Drevinge C.、Gustafsson K. L.、Corciulo C.、Lawenius L.、Iwakura Y.、Sj?gren K.、Lagerquist M. K.、Carlsten H.、Ohlsson C.、Islander U.
  • Journal Title: Scientific Reports Volume: 10 Pages: -
  • DOI: 10.1038/s41598-020-62562-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of U11snRNA as an Endogenous Agonist of TLR7-mediated Immune Pathogenesis (2019)
  • Author(s): Negishi H、 Endo H、 Nakajima Y、 Nishiyama T、 Tabunoki Y、 Nishio J、 Koshiba R、 Matsuda A、 Matsuki K、 Okamura T、 Negishi-Koga T、 Ichinohe T、 Takemura A、 Ishiwata H、 Iemura S、 Natsume T、 Abe T、 Kiyonari H、 Doi T、 Hangai S、 Yanai H、 Fujio K、 Yamamoto K、 Taniguchi T
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 116 Pages: 23653-23661
  • DOI: 10.1073/pnas.1915326116
  • Peer Reviewed
• [Journal Article] CD4+CD25+LAG3+ T Cells With a Feature of Th17 Cells Associated With Systemic Lupus Erythematosus Disease Activity (2019)
  • Author(s): Kato Rika、Sumitomo Shuji、Tsuchida Yumi、Tsuchiya Haruka、Nakachi Shinichiro、Sakurai Keiichi、Hanata Norio、Nagafuchi Yasuo、Kubo Kanae、Tateishi Shoko、Kanda Hiroko、Okamura Tomohisa、Yamamoto Kazuhiko、Fujio Keishi
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 1619-1619
  • DOI: 10.3389/fimmu.2019.01619
  • Peer Reviewed
• [Journal Article] Metabolism as a key regulator in the pathogenesis of systemic lupus erythematosus (2019)
  • Author(s): Takeshima Yusuke、Iwasaki Yukiko、Fujio Keishi、Yamamoto Kazuhiko
  • Journal Title: Seminars in Arthritis and Rheumatism Volume: 48 Pages: 1142～1145
  • DOI: 10.1016/j.semarthrit.2019.04.006
  • Peer Reviewed
• [Journal Article] Immune Profiling and Precision Medicine in Systemic Lupus Erythematosus (2019)
  • Author(s): Nagafuchi Yasuo、Shoda Hirofumi、Fujio Keishi
  • Journal Title: Cells Volume: 8 Pages: 140～140
  • DOI: 10.3390/cells8020140
  • Peer Reviewed
• [Journal Article] Dectin-2 Mediated Signaling Leads to Delayed Skin Wound Healing through Enhanced Neutrophilic Inflammatory Response and Neutrophil Extracellular Trap Formation (2019)
  • Author(s): Miura Takayuki、Kawakami Kazuyoshi、Kanno Emi、Tanno Hiromasa、Tada Hiroyuki、Sato Noriko、Masaki Airi、Yokoyama Rin、Kawamura Kotone、Kitai Yuki、Takagi Naoyuki、Yamaguchi Kenji、Yamaguchi Natsuki、Kyo Yoshika、Ishii Keiko、Imai Yoshimichi、Saijo Shinobu、Iwakura Yoichiro、Tachi Masahiro
  • Journal Title: Journal of Investigative Dermatology Volume: 139 Pages: 702～711
  • DOI: 10.1016/j.jid.2018.10.015
  • Peer Reviewed
• [Journal Article] Dectin-1 Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration (2019)
  • Author(s): Fan Qin、Tao Rong、Zhang Hang、Xie Hongyang、Lu Lin、Wang Ting、Su Min、Hu Jian、Zhang Qi、Chen Qiujing、Iwakura Yoichiro、Shen Weifeng、Zhang Ruiyan、Yan Xiaoxiang
  • Journal Title: Circulation Volume: 139 Pages: 663～678
  • DOI: 10.1161/CIRCULATIONAHA.118.036044
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Epidermal loss of phospholipase Cδ1 attenuates irritant contact dermatitis (2019)
  • Author(s): Shiratori Kanako、Kanemaru Kaori、Ogura Takahiro、Nakajima Aya、Sugizaki Yuko、Fukuyama Takatsugu、Iwakura Yoichiro、Nakamura Yoshikazu、Fukami Kiyoko
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 511 Pages: 330～335
  • DOI: 10.1016/j.bbrc.2019.02.046
  • Peer Reviewed
• [Journal Article] IL-1β Plays an Important Role in Pressure Overload-Induced Atrial Fibrillation in Mice (2019)
  • Author(s): Matsushita Naoko、Ishida Nanae、Ibi Miho、Saito Maki、Takahashi Masafumi、Taniguchi Shunichiro、Iwakura Yoichiro、Morino Yoshihiro、Taira Eiichi、Sawa Yohei、Hirose Masamichi
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 42 Pages: 543～546
  • DOI: 10.1248/bpb.b18-00363
  • Peer Reviewed
• [Journal Article] Spontaneous atopic dermatitis in mice with a defective skin barrier is independent of ILC2 and mediated by IL‐1β (2019)
  • Author(s): Schwartz Christian、Moran Tara、Saunders Sean P.、Kaszlikowska Agnieszka、Floudas Achilleas、Bom Joana、Nunez Gabriel、Iwakura Yoichiro、O’Neill Luke、Irvine Alan D.、McKenzie Andrew N. J.、Ogg Graham、Walsh Patrick T.、Demengeot Jocelyne、Fallon Padraic G.
  • Journal Title: Allergy Volume: 74 Pages: 1920～1933
  • DOI: 10.1111/all.13801
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Myeloid C‐type lectin receptors in skin/mucoepithelial diseases and tumors (2019)
  • Author(s): Tang Ce、Makusheva Yulia、Sun Haiyang、Han Wei、Iwakura Yoichiro
  • Journal Title: Journal of Leukocyte Biology Volume: 106 Pages: 903～917
  • DOI: 10.1002/JLB.2RI0119-031R
  • Peer Reviewed
• [Journal Article] Uncoupling the Senescence-Associated Secretory Phenotype from Cell Cycle Exit via Interleukin-1 Inactivation Unveils Its Protumorigenic Role (2019)
  • Author(s): Lau Lena、Porciuncula Angelo、Yu Alex、Iwakura Yoichiro、David Gregory
  • Journal Title: Molecular and Cellular Biology Volume: 39 Pages: -
  • DOI: 10.1128/MCB.00586-18
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment (2019)
  • Author(s): Drummond Rebecca A.、Swamydas Muthulekha、Oikonomou Vasileios、Zhai Bing、Dambuza Ivy M.、Schaefer Brian C.、Bohrer Andrea C.、Mayer-Barber Katrin D.、Lira Sergio A.、Iwakura Yoichiro、Filler Scott G.、Brown Gordon D.、Hube Bernhard、Naglik Julian R.、Hohl Tobias M.、Lionakis Michail S.
  • Journal Title: Nature Immunology Volume: 20 Pages: 559～570
  • DOI: 10.1038/s41590-019-0377-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Large Scale Calcium Imaging of the Cerebellar Vermis During Sensory Stimulus Unravels Two Response’s Components That Differ in Their Spatiotemporal Properties (2019)
  • Author(s): Byk Hananel、Huang Guo-Jen、Iwakura Yoichiro、Yarom Yosef
  • Journal Title: Frontiers in Systems Neuroscience Volume: 13 Pages: -
  • DOI: 10.3389/fnsys.2019.00018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dectin-2 induced CCL2 production in tissue-resident macrophages ignites cardiac arteritis (2019)
  • Author(s): Miyabe Chie、Miyabe Yoshishige、Bricio-Moreno Laura、Lian Jeffrey、Rahimi Rod A.、Miura Noriko N.、Ohno Naohito、Iwakura Yoichiro、Kawakami Tamihiro、Luster Andrew D.
  • Journal Title: Journal of Clinical Investigation Volume: 129 Pages: 3610～3624
  • DOI: 10.1172/JCI123778
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CCR8 leads to eosinophil migration and regulates neutrophil migration in murine allergic enteritis (2019)
  • Author(s): Blanco-P?rez Frank、Kato Yoichiro、Gonzalez-Menendez Irene、Laino Jonathan、Ohbayashi Masaharu、Burggraf Manja、Krause Maren、Kirberg J?rg、Iwakura Yoichiro、Martella Manuela、Quintanilla-Martinez Leticia、Shibata Noriyuki、Vieths Stefan、Scheurer Stephan、Toda Masako
  • Journal Title: Scientific Reports Volume: 9 Pages: -
  • DOI: 10.1038/s41598-019-45653-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] AIM2 inflammasome-derived IL-1β induces postoperative ileus in mice (2019)
  • Author(s): Hupa Kristof Johannes、Stein Kathy、Schneider Reiner、Lysson Mariola、Schneiker Bianca、Hornung Veit、Latz Eicke、Iwakura Yoichiro、Kalff J?rg C.、Wehner Sven
  • Journal Title: Scientific Reports Volume: 9 Pages: -
  • DOI: 10.1038/s41598-019-46968-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis (2019)
  • Author(s): 106.Sakurai, K., Dainichi, T., Garcet, S., Tsuchiya, S., Yamamoto, Y., Kitoh, A., Honda, T., Nomura, T., Egawa, G., Otsuka, A., Nakajima, S., Matsumoto, R., Nakano, Y., Otsuka, M., Iwakura, Y., Grinberg-Bleyer, Y., Ghosh, S., Sugimoto, Y., Guttman-Yassky, E., Krueger, J. G., and Kabashima, K.
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 144 Pages: 1036～1049
  • DOI: 10.1016/j.jaci.2019.06.019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Defect of Interferon γ Leads to Impaired Wound Healing through Prolonged Neutrophilic Inflammatory Response and Enhanced MMP-2 Activation (2019)
  • Author(s): Kanno Emi、Tanno Hiromasa、Masaki Airi、Sasaki Ayako、Sato Noriko、Goto Maiko、Shisai Mayu、Yamaguchi Kenji、Takagi Naoyuki、Shoji Miki、Kitai Yuki、Sato Ko、Kasamatsu Jun、Ishii Keiko、Miyasaka Tomomitsu、Kawakami Kaori、Imai Yoshimichi、Iwakura Yoichiro、Maruyama Ryoko、Tachi Masahiro、Kawakami Kazuyoshi
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Pages: 5657～5657
  • DOI: 10.3390/ijms20225657
  • Peer Reviewed
• [Presentation] 低分子βグルカンによる腸管免疫の制御 (2020)
  • Author(s): 岩倉洋一郎
  • Organizer: βグルカン協議会セミナー
  • Invited
• [Presentation] 免疫系の分子生物学と共に40年；学問の喜びと価値 (2019)
  • Author(s): 谷口 維紹
  • Organizer: 国立研究開発法人 医薬基盤・健康・栄養研究所 講演会
  • Invited
• [Presentation] 新学術領域研究学術研究支援基盤形成「先端モデル動物支援プラットフォーム」若手支援技術講習会 講演 (2019)
  • Author(s): 谷口 維紹
  • Organizer: 文部科学省科学研究費補助金 新学術領域研究学術研究支援基盤形成「先端モデル動物支援プラットフォーム」若手支援技術講習会
  • Invited
• [Presentation] DAMP molecules in the regulation of immunity, inflammation and cancer (2019)
  • Author(s): Tadatsugu Taniguchi
  • Organizer: International Congress of Immunology
  • Int'l Joint Research / Invited
• [Presentation] Identification of a new DAMP RNA that activates the TLR7 pathway (2019)
  • Author(s): Tadatsugu Taniguchi
  • Organizer: 9th International DAMPs and Alarmins Symposium
  • Int'l Joint Research / Invited
• [Presentation] The role of CTRP family members in the immune system. (2019)
  • Author(s): Yoichiro Iwakura
  • Organizer: The 30th Anniversary International Symposium of Research Institute for Biomedical Sciences, Tokyo University of Science
• [Presentation] Roles of C-type lectins in the homeostasis of the intestinal immunity. (2019)
  • Author(s): Yoichiro Iwakura
  • Organizer: NIH-Japan Joint Symposium
  • Int'l Joint Research / Invited
• [Presentation] Autoimmunity and B cells (2019)
  • Author(s): Keishi Fujio
  • Organizer: The 48th Annual Meeting of The Japanese Society for Immunology
  • Invited
• [Presentation] Functional genomics reveals cell metabolism alteration of B cells in systemic lupus erythematosus (2019)
  • Author(s): Keishi Fujio
  • Organizer: The 48th Annual Meeting of The Japanese Society for Immunology
  • Invited
• [Book] EXPERT膠原病・リウマチ 改訂第4版 (2019)
  • Author(s): 20.角田茂、岩倉洋一郎
  • Total Pages: 416
  • Publisher: 診断と治療社
  • ISBN: 978-4787823830
• [Patent(Industrial Property Rights)] 免疫機能を調節する核酸分子およびその用途 (2019)
  • Inventor(s): 谷口維紹
  • Industrial Property Rights Holder: 谷口維紹
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2019-105748