Comprehensive understandings of extracellular nucleotides for mucosal healing and inflammation

• Project/Area Number: 18KK0432
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Chiba University
• Principal Investigator: Kurashima Yosuke 千葉大学, 大学院医学研究院, 准教授 (30729372)
• Project Period (FY): 2019 – 2022
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
• Keywords: 細胞外核酸 / アデノシン3リン酸 / 線維芽細胞 / 糖ヌクレオチド / 間葉系細胞 / 腸管感染症 / 粘膜免疫 / 炎症性腸疾患 / 微小環境 / 平滑筋 / 病原性細菌 / 感染防御 / 粘膜修復 / ATP

Outline of Research at the Start

炎症性腸疾患の治療においては、現行の炎症コントロールのみならず腸管の「粘膜修復・再生」に特化した創薬が次世代治療に不可欠である。複数の細胞集団から構成される「間葉系細胞」は粘膜治癒に中心的に働くと考えられているが、一方で、これらの細胞集団による粘膜保護機能を有益に活用する方法は確立されていない。本研究では、間葉系細胞に高く発現する細胞外の核酸に対する受容体群に着目し、領域を牽引するカルフォルニア大学サンディエゴ校のPeter Ernst教授らとの共同研究を通じで、細胞外核酸を介した粘膜炎症・修復機序を明らかにする。

Outline of Final Research Achievements

We have established a method for isolating mesenchymal cells, controlling the differentiation of epithelial stem cells, from the intestinal crypt. Using this experimental method, we were able to compare the gene expression between mesenchymal cells present in the other intestinal microenvironment. As a result, we discovered that specific receptors for extracellular pyrimidines or sugar nucleotides, as well as certain adenosine receptors, are highly expressed in the mesenchymal cells in the crypt. Therefore, through this international collaborative research, we conducted profiling of extracellular nucleic acids and further elucidated the role of extracellular nucleic acids that act on mesenchymal cells in mucosal repair and protection processes through in vitro and in vivo analyses using various gene knockout mice.

Academic Significance and Societal Importance of the Research Achievements

マウス腸管における細胞外核酸並びに糖ヌクレオチド受容体の発現細胞についてプロファイリングを進めた結果、特に糖ヌクレオチドが特定の間葉系細胞で発現していることを見出している。また、プロファイリング結果はヒトの腸管組織においても同様の結果であった。
加えて、腸内細菌による腸管の低酸素環境の形成をはじめとした腸内環境の変動によって、受容体の発現が調整されることを見出した。特に、免疫細胞の遊走や集積に関わる因子がこの受容体刺激を介して導かれていることも明らかとなり、糖ヌクレオチドならびに発現細胞は、腸管感染症から生体防御において重要な役割を担っていることが明らかとなった。

Research Products

• [Int'l Joint Research] カルフォルニア大学(米国) (2022)
• [Int'l Joint Research] カルフォルニア大学(米国) (2019)
• [Journal Article] Nasal vaccines: solutions for respiratory infectious diseases (2023)
  • Author(s): Nakahashi-Ouchida Rika、Fujihashi Kohtaro、Kurashima Yosuke、Yuki Yoshikazu、Kiyono Hiroshi
  • Journal Title: Trends in Molecular Medicine Volume: 29 Issue: 2 Pages: 124-140
  • DOI: 10.1016/j.molmed.2022.10.009
  • Peer Reviewed / Open Access
• [Journal Article] Increased Myosin light chain 9 expression during Kawasaki disease vasculitis (2023)
  • Author(s): Kobayashi Hironobu、Kimura Motoko Y.、Hasegawa Ichita、Suganuma Eisuke、Ikehara Yuzuru、Azuma Kazuhiko、Ito Toshihiro、Ebata Ryota、Kurashima Yosuke、Kawasaki Yohei、Shiko Yuki、Saito Naoki、Iwase Hirotaro、Lee Youngho、Noval Rivas Magali、Arditi Moshe、Zuka Masahiko、Hamada Hiromichi、Nakayama Toshinori
  • Journal Title: Frontiers in Immunology Volume: 13
  • DOI: 10.3389/fimmu.2022.1036672
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Utilizing mast cells in a positive manner to overcome inflammatory and allergic diseases. (2022)
  • Author(s): Zhang Z., Ernst P.B., Kiyono H., Kurashima Y.
  • Journal Title: 13 Volume: 13 Pages: 937120-937120
  • DOI: 10.3389/fimmu.2022.937120
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intestinal homeostasis and inflammation: Gut microbiota at the crossroads of pancreas?intestinal barrier axis (2022)
  • Author(s): Zhang Z., Tanaka I., Pan Z., Ernst P.B., Kiyono H., Kurashima Y.
  • Journal Title: European Journal of Immunology Volume: 52 Issue: 7 Pages: 1035-1046
  • DOI: 10.1002/eji.202149532
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of adrenaline auto-injector prescription profiles: A population-based, retrospective cohort study within the National Insurance Claims Database of Japan (2022)
  • Author(s): Sato Sakura、Kainuma Keigo、Noda Tatsuya、Ebisawa Motohiro、Futamura Masaki、Imamura Tomoaki、Miyagawa Akihiro、Nakajima Saeko、Ogawa Yasushi、Inomata Takenori、Kan-o Keiko、Kurashima Yosuke、Masaki Katsunori、Myojin Tomoya、Nishioka Yuichi、Sakashita Masafumi、Tamari Mayumi、Morita Hideaki、Adachi Takeya
  • Journal Title: Allergology International Volume: 71 Issue: 3 Pages: 354-361
  • DOI: 10.1016/j.alit.2022.02.002
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Research impact analysis of international funding agencies in the realm of allergy and immunology. (2022)
  • Author(s): Adachi T, Ogawa Y, Fukushi T, Ito K, Koizumi A, Shirabe M, Toriya M, Hirako J, Inomata T, Masaki K, Sasano R, Sato S, Kainuma K, Futamura M, Kan-o K, Kurashima Y, Nakajima S, Sakashita M, Morita H, Iwamoto A, Nishima S, Tamari M, Iizuka H
  • Journal Title: Allergy Volume: 77 Issue: 5 Pages: 1602-06
  • DOI: 10.1111/all.15249
  • Peer Reviewed / Open Access
• [Journal Article] Pancreatic glycoprotein 2 is a first line of defense for mucosal protection in intestinal inflammation (2021)
  • Author(s): Kurashima Yosuke、Kigoshi Takaaki、Murasaki Sayuri、Arai Fujimi、Shimada Kaoru、Seki Natsumi、Kim Yun-Gi、Hase Koji、Ohno Hiroshi、Kawano Kazuya、Ashida Hiroshi、Suzuki Toshihiko、Morimoto Masako、Saito Yukari、Sasou Ai、Goda Yuki、Yuki Yoshikazu、Inagaki Yutaka、Iijima Hideki、Suda Wataru、Hattori Masahira
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 1067-1067
  • DOI: 10.1038/s41467-021-21277-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Orally desensitized mast cells form a regulatory network with Treg cells for the control of food allergy. (2021)
  • Author(s): Takasato Y, Kurashima Y, Kiuchi M, Hirahara K, Murasaki S, Arai F, Izawa K, Kaitani A, Shimada k, Saito Y, Toyoshima S, Nakamura M, Fujisawa K, Okayama Y, Kunisawa J, Kubo M, Takemura N, Uematsu S, Akira S, Kitaura J, Takahashi T, Nakayama T, Kiyono H
  • Journal Title: Mucosal Immunol Volume: 14 Issue: 3 Pages: 640-651
  • DOI: 10.1038/s41385-020-00358-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stratified layer analysis reveals intrinsic leptin stimulates cryptal mesenchymal cells for controlling mucosal inflammation (2020)
  • Author(s): Matsumura Seiichi、Kurashima Yosuke、Murasaki Sayuri、Morimoto Masako、Arai Fujimi、Saito Yukari、Katayama Nana、Kim Dayoung、Inagaki Yutaka、Kudo Takahiro、Ernst Peter B.、Shimizu Toshiaki、Kiyono Hiroshi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 18351-18351
  • DOI: 10.1038/s41598-020-75186-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A role for the CCR5?CCL5 interaction in the preferential migration of HSV-2-specific effector cells to the vaginal mucosa upon nasal immunization (2019)
  • Author(s): Joo Sunyi、Suwanto Aldina、Sato Ayuko、Nakahashi-Ouchida Rika、Mori Hiromi、Uchida Yohei、Sato Shintaro、Kurashima Yosuke、Yuki Yoshikazu、Fujihashi Kohtaro、Kawaguchi Yasushi、Kiyono Hiroshi
  • Journal Title: Mucosal Immunology Volume: 12 Issue: 6 Pages: 1391-1403
  • DOI: 10.1038/s41385-019-0203-z
  • Peer Reviewed / Open Access
• [Journal Article] Mast cells play role in wound healing through the ZnT2/GPR39/IL-6 axis (2019)
  • Author(s): Nishida K, Hasegawa A, Yamasaki S, Uchida R, Ohashi W, Kurashima Y, Kunisawa J, Kimura S, Iwanaga T, Watarai H, Hase K, Ogura H, Nakayama M, Kashiwakura J, Okayama Y, Kubo M, Ohara O, Kiyono H, Koseki H, Murakami M, Hirano T
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 10842-10842
  • DOI: 10.1038/s41598-019-47132-5
  • Peer Reviewed / Open Access
• [Journal Article] Intrinsic Control of Surface Immune and Epithelial Homeostasis by Tissue-Resident Gut Stromal Cells (2019)
  • Author(s): Kurashima Yosuke、Tokuhara Daisuke、Kamioka Mariko、Inagaki Yutaka、Kiyono Hiroshi
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 01281-01281
  • DOI: 10.3389/fimmu.2019.01281
  • Peer Reviewed / Open Access
• [Presentation] Elucidation of mucosal defense mechanism by hierarchical support system of digestive tract (2023)
  • Author(s): Yosuke Kurashima
  • Organizer: International Symposium for Future Mucosal Vaccines: Safeguards and Innovations against Infectious Diseases
  • Int'l Joint Research / Invited
• [Presentation] Spatially Organized Multicellular Mesenchymal-Neural Hubs in Intestinal Mucosa (2023)
  • Author(s): Yosuke Kurashima
  • Organizer: cSIMVA Workshop
  • Int'l Joint Research / Invited
• [Presentation] Identification of Pancreas GP2-binding Bacteria and Elucidation of its Pathogenicity in Intestinal Inflammation (2023)
  • Author(s): Zhongwei Zhang, Zhen Pan, Yukari Saito, Izumi Tanaka, Amber Black, Peter B Erns, Hiroshi Kiyono, Yosuke Kurashima
  • Organizer: cSIMVA Workshop
  • Int'l Joint Research
• [Presentation] Elucidation of Disease-associated Mesenchymal Cells in the Tissue Microenvironment in Mice Colon (2023)
  • Author(s): Izumi Tanaka, Sayuri Murasaki, Zhongwei Zhang, Amber Black, Peter B Ernst, Hiroshi Kiyono, Yosuke Kurashima
  • Organizer: cSIMVA Workshop
  • Int'l Joint Research
• [Presentation] 臓器・細胞連関による腸管粘膜保護 (2023)
  • Author(s): 倉島 洋介
  • Organizer: SAMURAI研究会 3rd
  • Invited
• [Presentation] Gut Microbiota at the Crossroads of Pancreas-Intestinal Barrier Axis (2023)
  • Author(s): 倉島 洋介
  • Organizer: 第100回日本生理学会大会
  • Invited
• [Presentation] 腸管バリア機能を強化する Lactobacillus 株のスクリーニングと有効性の検証 (2022)
  • Author(s): 倉島 洋介
  • Organizer: 第22回DIJFカンファランス
  • Invited
• [Presentation] マスト細胞のアレルゲンセンシング ～脱感作と抗アレルギー機能～ (2022)
  • Author(s): 倉島 洋介
  • Organizer: 日本食品免疫学会第18回学術大会
  • Invited
• [Presentation] 食物アレルギー減感作療法における マスト細胞のフェノタイプ変化 (2022)
  • Author(s): 倉島 洋介
  • Organizer: 第71回日本アレルギー学会学術大会
  • Invited
• [Presentation] 膵による腸管感染防御機構 (2022)
  • Author(s): 倉島 洋介
  • Organizer: 第65回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] Pancreatic-Gut Axis for the Mucosal Protection (2021)
  • Author(s): 倉島 洋介
  • Organizer: Joint Seminar of ‘Chiba University Tenure Track Seminar Program and International Research and Development Center for Mucosal Vaccines (IMSUT) Vaccine Center Seimnar’
  • Invited
• [Presentation] 腸内細菌の制御を担う新たな「膵臓」の役割 (2020)
  • Author(s): 倉島 洋介、清野 宏
  • Organizer: 第24回腸内細菌学会
  • Invited
• [Presentation] Bringing mucosal mast cells over to our side to overcome allergy (2019)
  • Author(s): Yosuke Kurashima
  • Organizer: World Allergy Congress 2019
  • Int'l Joint Research / Invited
• [Presentation] Elucidation of novel pathways in the mucosal protection in the gut (2019)
  • Author(s): Yosuke Kurashima
  • Organizer: CU-UCSD Center for Mucosal Immunology, Allergy and Vaccine Development Seminar
  • Int'l Joint Research / Invited
• [Presentation] Novel roles of accessory digestive organ in mucosal protection (2019)
  • Author(s): Yosuke Kurashima
  • Organizer: JSPS-Crick Symposium on Gut Circuits. London
  • Int'l Joint Research / Invited
• [Book] 胆と膵, 44(3) 229-234, 腸内細菌の制御を担う膵臓の役割 (2023)
  • Author(s): 倉島洋介
  • Publisher: 医学図書出版
  • ISBN: 9784865175202
• [Book] 肝胆膵, 86(3) 369-376, マイクロバイオームと膵腸連関 (2023)
  • Author(s): 倉島洋介, 清野宏
  • Publisher: アークメディア