Multi Regulatory System for Gut Homeostasis and Inflammation

2018 Fiscal Year Annual Research Report

• Project/Area Number: 18H05280
• Research Institution: The University of Tokyo
• Principal Investigator: 清野 宏 東京大学, 医科学研究所, 特任教授 (10271032)
• Co-Investigator(Kenkyū-buntansha): 倉島 洋介 千葉大学, 大学院医学研究院, 准教授 (30729372)
• Project Period (FY): 2018-06-11 – 2023-03-31
• Keywords: 粘膜免疫 / 膵臓 / パネート細胞 / 間葉系細胞 / 陰窩 / 抗菌ペプチド / 炎症性腸疾患 / 腸間膜脂肪

Outline of Annual Research Achievements

本研究は、腸管粘膜での炎症疾患およびその合併症の病態形成機構の解明を目的としており、3つの研究小課題を設けて研究を進めている。研究開始初年度では、3つの研究小課題のうち、①「粘膜―間葉系連関」②「腸－膵連関」の2つの研究項目に進捗があったため、下記にその概要を記す。
① 「粘膜―間葉系連関」
腸管陰窩の幹細胞ニッチの維持には、パネート細胞と間葉系細胞から産生されるWnt関連分子が重要である。小腸においてはパネート細胞が責任細胞として働き、一方で大腸においては陰窩もしくは辺縁部に局在する間葉系細胞がその働きを担う。本年度は、腸管の各部位（十二指腸、空腸、回腸）からパネート細胞を単離し、幹細胞ニッチに関わる遺伝子群並びに抗菌ペプチドの発現についての網羅的な解析を行った。その結果、パネート細胞には、Wnt等のサイトカイン産生能を保持した細胞集団と、ディフェンシン等の抗菌ペプチド産生能が高い集団に分けられることが示された。
②「腸－膵連関」研究では、粘膜保護臓器としての膵臓という視点で解析を進めており、本年度は、膵臓特異的Creマウスの導入と膵臓腺房細胞の培養系の確立を行った。既報では、腸管上皮のマーカー遺伝子である「Villin１」が膵臓腺房細胞に発現しているとされていた。そこで、Villin1-Cre・Rosa-tdTomatoマウスを作出した。しかしながら、既報とは異なり膵臓にvillin1のシグナルは検出されなかったため、腺房細胞の解析には用いられないことが示された。そこで、新たにPtf1aコンディショナルマウスを導入し、解析を行ったところ、腺房細胞特異的であることが確認された。同時に、当該マウスを用いて腺房細胞の培養系の精度を確認した。今後膵臓腺房細胞特異的マウスを用いてin vivo、ex vivoの実験系を駆使し膵臓由来の粘膜保護因子分泌機序についての解析を進める。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

本年度の研究から、パネート細胞には、Wnt等のサイトカイン産生能に特化した細胞集団と、ディフェンシン等の抗菌ペプチド産生能が高い細胞集団に分けられることが示された。これまでサブセットや機能的分類をされてこなかったパネート細胞に、上記のような亜群の存在が示唆されたことは非常に画期的な発見であり、次年度以降の更なる発展が期待できる。また、膵臓腺房細胞コンディショナルマウスの導入並びに解析系が樹立しており、本研究課題の遂行に必要な解析手法は確立済である。

Strategy for Future Research Activity

本研究課題では、①「腸－膵連関」、②「粘膜―間葉系連関」、③「粘膜－筋層連関」の３つの項目について解析を進め、それぞれの研究項目で作製予定である連関システムの破綻モデル動物の融合を試みている。「研究実績の概要」項目で述べたとおり、網羅的遺伝子解析ならびにコンディショナルマウスの導入が当初の予定通り進んでおり、得られたデータをもとに、新規性の高い、独自のモデルマウスの構築が期待できる。

Research Products

• [Journal Article] New trends in mucosal immunology and allergy. (2019)
  • Author(s): Kiyono, H. Izuhara, K.
  • Journal Title: Allergol Int. Volume: 68.1 Pages: 1-3
  • DOI: 10.1016/j.alit.2018.12.002.
  • Peer Reviewed
• [Journal Article] Dietary coconut oil ameliorates skin contact hypersensitivity through mead acid production in mice. (2019)
  • Author(s): Tiwari, P., Nagatake, T., Hirata, S.I., Sawane, K, Saika, A., Shibata, Y., Morimoto, S., Honda, T., Adachi, J., Abe, Y., Isoyama, J., Tomonaga, T., Kiyono, H., Kabashima, K. Kunisawa, J.
  • Journal Title: Allergy Volume: Epub ahead of print Pages: －
  • DOI: 10.1111/all.13762.
  • Peer Reviewed
• [Journal Article] Distinct Roles for Peyer's Patch B Cells for Induction of Antigen-specific IgA Antibody Responses in Mice Administered Oral Recombinant Salmonella. (2019)
  • Author(s): Hashizume-Takizawa, T., Shibata, N., Kurashima, Y., Kiyono, H., Kurita-Ochiai, T. Fujihashi, K.
  • Journal Title: Int Immunol Volume: Epub ahead of print Pages: －
  • DOI: 10.1093/intimm/dxz029.
  • Peer Reviewed
• [Journal Article] A comprehensive understanding of the gut mucosal immune system in allergic inflammation. (2019)
  • Author(s): Tokuhara, D., Kurashima, Y., Kamioka, M., Nakayama, T., Ernst, P. Kiyono, H.
  • Journal Title: Allergol Int. Volume: 68.1 Pages: 17-25
  • DOI: 10.1016/j.alit.2018.09.004.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Current status and future directions of study on glycosylation for gut microbiota and the mucosal immune network. (2019)
  • Author(s): Goto, Y., Kiyono, H.
  • Journal Title: Glycoscience: Basic Science to Applications - Insights from the Japan Consortium. Volume: Mar2019 Pages: 92-94
  • DOI: NA
• [Journal Article] Development of immune and microbial environments is independently regulated in the mammary gland. (2018)
  • Author(s): Niimi, K., Usami, K., Fujita, Y., Abe, M., Furukawa, M., Suyama, Y., Sakai, Y., Kamioka, M., Shibata, N., Park, EJ., Sato, S., Kiyono, H., Yoneyama, H., Kitazawa, H., Watanabe, K., Nochi, T., Aso, H.
  • Journal Title: Mucosal Immunol Volume: 11.3 Pages: 643-653
  • DOI: 10.1038/mi.2017.90.
  • Peer Reviewed
• [Journal Article] Lymphoid tissue-resident Alcaligenes LPS induces IgA production without excessive inflammatory responses via weak TLR4 agonist activity (2018)
  • Author(s): Shibata, N., Kunisawa, J., Hosomi, K., Fujimoto, Y., Mizote, K., Kitayama, N., Shimoyama, A., Mimuro, H., Sato, S., Kishishita, N., Ishii, KJ., Fukase, K., Kiyono, H.
  • Journal Title: Mucosal Immunol Volume: 11.3 Pages: 693-702
  • DOI: 10.1038/mi.2017.103.
  • Peer Reviewed
• [Journal Article] Human norovirus propagation in human induced pluripotent stem cell-derived intestinal epithelial cells. (2018)
  • Author(s): Sato, S., Hisaie, K., Kurokawa, S., Suzuki, A., Sakon, N., Uchida, Y., Yuki, Y., Kiyono, H.
  • Journal Title: Cell Mol Gastroenterol Hepatol. Volume: S2352-345X.18 Pages: 164-4
  • DOI: 10.1016/j.jcmgh.2018.11.001.
  • Peer Reviewed
• [Journal Article] The 17,18-epoxyeicosatetraenoic acid-G protein-coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques by inhibiting neutrophil mobility in mice and cynomolgus macaques. (2018)
  • Author(s): Nagatake, T., Shiogama, Y., Inoue, A., Kikuta, J., Honda, T., Tiwari, P., Kishi, T., Yanagisawa, A., Isobe, Y., Matsumoto, N., Shimojou, M., Morimoto, S., Suzuki, H., Hirata, S., Steneberg, P., Edlund, H., Aoki, J., Arita, M., Kiyono, H., Yasutomi, Y., Ishii, M., Kabashima, K. Kunisawa, J.
  • Journal Title: J Allergy Clin Immunol. Volume: 142.2 Pages: 470-484
  • DOI: 10.1016/j.jaci.2017.09.053.
  • Peer Reviewed
• [Journal Article] ATP as a pathophysiologic mediator of bacteria-host crosstalk in the gastrointestinal tract. (2018)
  • Author(s): Inami, A., Kiyono, H., Kurashima, Y.
  • Journal Title: Int J Mol Sci. Volume: 19.8 Pages: 2371
  • DOI: 10.3390/ijms19082371.
  • Peer Reviewed / Open Access
• [Journal Article] 共生と排除を司る粘膜マスト細胞 (2018)
  • Author(s): 倉島洋介
  • Journal Title: 腸内細菌学雑誌 Volume: 32 Pages: 159-166
  • DOI: NA
• [Presentation] Orally-desensitized mast cells acquired regulatory characteristics for the control of allergy (2019)
  • Author(s): Kurashima, Y.
  • Organizer: 3rd Annual Symposium for the Center for Mucosal Immunology, Allergy and Vaccine Development
  • Int'l Joint Research
• [Presentation] The Mucosal Immune System for Symbiosis, Elimination and Vaccine (2019)
  • Author(s): Kiyono, H.
  • Organizer: Interdisciplinary Seminar on Mucosal Immunology at Tohoku University.
• [Presentation] Mesenchymal-myeloid cell interactions in microenvironment for novel fibrogenic machinery in tissue fibrosis (2019)
  • Author(s): Kurashima, Y., Murasaki, S., Morimoto, M., Shimizu, K., Kiyono, H.
  • Organizer: 第3回千葉大学グローバルプロミネント研究基幹シンポジウム
• [Presentation] Gut-multi Ecosystem for Immunity, Inflammation and Vaccine (2018)
  • Author(s): Kiyono, H.
  • Organizer: UCSD Gastroenterology Tuesday Morning Conference, San Diego, CA, USA
  • Invited
• [Presentation] Metagenome Analysis; Great Impact on the Next-Generation Surveillance System for Diarrheal and HIV Diseases (2018)
  • Author(s): Kiyono, H.
  • Organizer: Noguchi Hideyo Memorial Museum, Symposium on Infectious Disease and Immunity,
  • Int'l Joint Research / Invited
• [Presentation] Mucosal Equilibrium of Immunity and Symbiosis: From Basic to Vaccine Development (2018)
  • Author(s): Kiyono, H.
  • Organizer: University of Florida, Florida, USA
  • Int'l Joint Research / Invited
• [Presentation] Mucosal Multi-Ecological Loop of Intra- and Extra-Tissue Commensal Microbiota, Epithelial Cells and Immune Cells for Gut Homeostasis and InflammationMucosal Multi-Ecological Loop of Intra- and Extra-Tissue Commensal Microbiota, Epithelial Cells and Immune Cells for Gut Homeostasis and Inflammation (2018)
  • Author(s): Kiyono, H.
  • Organizer: TOLLerant final event "Microbiota/host dialogue, the molecular language”
  • Invited
• [Presentation] “Mucosal Immunology: Mucosal Homeostasis, Development of Novel Oral Vaccines for Global Health (2018)
  • Author(s): Kiyono, H.
  • Organizer: CU-UCSD cMAV Symposium 2019, San Diego, USA
  • Invited
• [Presentation] Mucosal Multi-ecological System Creates Novel Strategy for the Prevention and Treatment of Diseases (2018)
  • Author(s): Kiyono, H.
  • Organizer: The 67th Annual Meeting of Japanese Society of Allergology
• [Presentation] The Mucosal Immune System for Symbiosis, Elimination and Vaccine (2018)
  • Author(s): Kiyono, H.
  • Organizer: Japanese Society of Immunology’s Immunology Summer School
• [Presentation] Intestine as a Super Immunological Organ (2018)
  • Author(s): Kiyono, H.
  • Organizer: Intercompany Seminar of Asahi Kogyosha Co., Ltd.
• [Presentation] Equilibrium of Immunity & Symbiosis: From Basic to Vaccine Development (2018)
  • Author(s): Kiyono, H.
  • Organizer: Max Plank Institute for Infection Biology Alumni Meeting
• [Presentation] Mucosal tissue axis for the induction and regulation of immunity, inflammation and symbiosis (2018)
  • Author(s): Kiyono, H.
  • Organizer: Japan-German Immunology Workshop,
• [Presentation] 小腸パイエル板組織内共生細菌アルカリゲネスの免疫機能とアジュバント応用 (2018)
  • Author(s): 柴田納央子、細見晃司、下山敦史、王韻茹、吉井健、深瀬浩一、清野宏、國澤純
  • Organizer: 第15回日本小児消化管感染症研究会
• [Presentation] 共生と排除を司る粘膜マスト細胞の研究/Elucidation of the function of mucosal mast cells for symbiosis and elimination (2018)
  • Author(s): 倉島洋介
  • Organizer: 第22回腸内細菌学会 受賞講演
  • Invited
• [Presentation] 間葉系細胞による免疫末梢教育/Mesenchymal-myeloid cell interactions in renal microenvironment for novel fibrogenic machinery in kidney fibrosis (2018)
  • Author(s): 倉島洋介
  • Organizer: 第42回日本リンパ学会
• [Presentation] Mesenchymal cell-mediated local inflammatory loop in intestinal inflammation (2018)
  • Author(s): Kurashima, Y.
  • Organizer: 2nd Korea-Japan Joint Meeting on Mucosal Immunology
• [Presentation] Bringing mast cells over to our side to overcome allergy” (2018)
  • Author(s): Kurashima, Y.
  • Organizer: 第67回日本アレルギー学会学術大会 シンポジウム18
  • Invited
• [Presentation] 腸管粘膜・皮膚などにおける上皮－間葉－神経系ネットワークによる末梢免疫教育機構 (2018)
  • Author(s): 倉島洋介
  • Organizer: アステラス製薬招待講演
• [Presentation] Synthesis and function of symbiotic bacterial lipopolysaccharide partial structures. (2018)
  • Author(s): Shimoyama, A., Mizote, K., Uto, T., Shibata, N., Lorenzo, F.D., Molinaro, A., Fujimoto, Y., Kunisawa, J., Kiyono, H., Fukase, K.,
  • Organizer: 5th Asian Chemical Biology Conference (Oral)
  • Int'l Joint Research
• [Presentation] Synthesis and Function of Symbiotic Bacterial Lipopolysaccharide Partial Structures, (2018)
  • Author(s): Shimoyama, A., Mizote, K., Uto, T., Shibata, N., Lorenzo F.D., Molinaro, A., Kunisawa, J., Kiyono, H., Fujimoto, Y., Fukase, K.
  • Organizer: Joint Meeting of the Society for Leukocyte Biology (SLB) & the International Endotoxin and Innate Immunity Society(IEIIS
  • Int'l Joint Research
• [Presentation] Synthesis and functions of symbiotic bacterial lipopolysaccharide partial structures. (2018)
  • Author(s): Shimoyama, A., Mizote, K., Uto, T., Lorenzo, F.D., Shibata, N., Fujimoto, Y., Kunisawa, J., Kiyono, K.
  • Organizer: MicrobiotaMi2018 Milano, Italy
• [Presentation] Synthesis and function of symbiotic bacterial lipopolysaccharide partial structures (2018)
  • Author(s): Shimoyama, A., Mizote, K., Uto, T., Shibata, N., Lorenzo, F.D., Molinaro, A., Fujimoto, Y., Kunisawa, J., Kiyono, H., Fukase, K.
  • Organizer: 5th Asian Chemical Biology Conference (Poster)
  • Int'l Joint Research
• [Presentation] Synthesis and immunological function of symbiotic bacterial lipopolysaccharide partial structures. (2018)
  • Author(s): Shimoyama, A., Mizote, K., Uto, T., Lorenzo, F.D., Shibata, N., Fujimoto, Y., Kunisawa, J., Kiyono, H., Molinaro, A. Fukase, K.
  • Organizer: The 14th International Kyoto Conference on New Aspects of Organic Chemistry (IKCOC14)
• [Presentation] CCL28-mediated chemotaxis for the recruitment of IgA-producing plasma cells into the mammary gland depends on the lactation-related but not bacterial stimulus (2018)
  • Author(s): Nochi, T., Niimi, K., Usami, K., Furukawa, M., Sasaki, S., Kiyono, H., Watanabe, K. and Aso, H.
  • Organizer: Mucosal Immunology Course & Symposium (MICS2018)
  • Int'l Joint Research
• [Presentation] 寄生・共生菌由来リポ多糖部分構造の合成と免疫調節機能の解明 (2018)
  • Author(s): 下山敦史、溝手啓介、宇戸智哉、柴田納央子、Flaviana Di Lorenzo、Antonio Molinaro、國澤純、清野宏、藤本ゆかり、深瀬浩一、
  • Organizer: 第37回日本糖質学会年会
• [Presentation] LPS from lymphoid tissue-resident Alcaligenes induces IgA without excessive inflammation via its weak TLR4 agonist activity (2018)
  • Author(s): Shibata, N., Kunisawa, J., Hosomi, K., Fujimoto, Y., Mizote, K., Kitayama, N., Shimoyama, A., Ishii, K.J., Fukase, K. and Kiyono, H.
  • Organizer: 第47回日本免疫学会
• [Presentation] 間葉系細胞による免疫恒常性維持機構 (2018)
  • Author(s): 倉島洋介, 松村成一, 村崎さゆり, 清野宏
  • Organizer: 第8回オルソオルガノジェネシス検討会
• [Presentation] Orally-desensitized mast cells acquired regulatory characteristics for the control of food allergy (2018)
  • Author(s): Kurashima, Y., Takasato, Y., Kiuchi, M., Hirahara, K., Murasaki, S., Kunisawa, J., Kubo, M., Uematsu, S., Nakayama, T., Kiyono, H.
  • Organizer: 第47回日本免疫学会学術集会
• [Book] Handbook of Immunosenescence: Basic Understanding and Clinical Implications (2019)
  • Author(s): Fujihashi, K., McGhee, J. R., and Kiyono, H.
  • Total Pages: NA
  • Publisher: Springer Science
  • ISBN: NA
• [Book] Lymph Node Metastasis in Gastrointestinal Cancer (2019)
  • Author(s): Nagatake, T., Kunisawa, J., and Kiyono, H.
  • Total Pages: NA
  • Publisher: Springer
  • ISBN: 978-981-10-4699-5
• [Book] 免疫生物学（原書第9版）(翻訳) (2019)
  • Author(s): 籠谷領二, 倉島洋介, 清野宏、
  • Total Pages: NA
  • Publisher: 南江堂
  • ISBN: NA
• [Book] SMI textbook of Principles of Mucosal Immunology. 2nd Edition. (2018)
  • Author(s): Kiyono, H., Fujihashi, K., Mestecky, J.
  • Total Pages: NA
  • Publisher: Garland Science, Taylor & Francis Group, LLC
  • ISBN: NA
• [Book] 腎臓内科・泌尿器科7 (2018)
  • Author(s): 山本智久、 倉島洋介、 清野宏
  • Total Pages: NA
  • Publisher: 科学評論社
  • ISBN: ISSN:2188-9147
• [Book] リンパ学41-2 (2018)
  • Author(s): 切真里奈, 清野宏, 倉島洋介
  • Total Pages: NA
  • Publisher: 日本リンパ学会
  • ISBN: NA