Dysfunction of mucosal immune education system in chronic inflammation

• Project/Area Number: 19H03450
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• 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): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2022: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 炎症性腸疾患 / 免疫末梢教育 / 線維芽細胞 / 間葉系細胞 / 慢性炎症 / 細胞間相互作用 / 粘膜免疫 / 線維化 / 臓器連関 / 蠕動運動 / 腸管免疫 / 微小環境 / マクロファージ / 顆粒球

Outline of Research at the Start

マスト細胞やマクロファージなどの免疫細胞は、組織・臓器の微小環境に応じて、生体にとって有益に働くように制御されている。申請者の独自の研究から、間葉系細胞と呼ばれる細胞集団が免疫細胞に対して、末梢組織で組織特異性を誘導していることがわかっており、これを「免疫末梢教育機構」と呼んでいる。一方で、線維化をはじめとした慢性炎症では「免疫末梢教育機構」が破綻しており、不適切な免疫細胞の恒常的活性化が起きている。
本研究では、間葉系細胞の機能破綻が導く免疫末梢教育の攪乱による組織破壊並びに腸管線維化についての解析を行う。

Outline of Final Research Achievements

Many types of immune cells are controlled to function appropriately depending on the microenvironment of tissues and organs, mediated by mesenchymal cells, which is known as "tissue specificity". Based on our research, the mechanism of inducing tissue specificity for the immune cells at peripheral site, called the "peripheral immune education system" has been revealed. On the other hand, it has been known that the function of mesenchymal cells is disrupted in chronic inflammation, such as excessive production of extracellular matrix, and it is speculated that disturbance of peripheral immune education system in the microenvironment occurs in this condition.
In this study, we aimed the identification of mesenchymal cells involved in intestinal fibrosis and the mechanisms of alteration of "peripheral immune education system" and it became clear that excessive activation of inflammatory cells is induced by the accumulation of ectopic mesenchymal cells in intestinal tissues.

Academic Significance and Societal Importance of the Research Achievements

間葉系細胞による末梢組織での免疫細胞の成熟様式である「免疫末梢教育機構」を明らかにすることは、組織恒常性の維持機構の理解と疾患発症における分子実態の解明につながる。
本研究から、線維化に関わる間葉系細胞が同定され、さらに細胞間相互作用並びに標的分子が見出された。さらに、実験動物モデルでの結果のみならず、ヒト検体を用いた解析からも同様の分子機構が腸炎の重症化に寄与している可能性が示唆されており、本研究課題による成果を基盤として、トランスレーショナルなアプローチによる更なる詳細な解析が期待される。

Research Products

• [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] Persistent colonization of non-lymphoid tissue-resident macrophages by Stenotrophomonas maltophilia (2019)
  • Author(s): Takahashi Ichiro, Hosomi Koji, Nagatake Takahiro, Tobou Hirokazu, Yamamoto Daiki, Hayashi Ikue, Kurashima Yosuke, Sato Shintaro, Shibata Naoko, Goto Yoshiyuki, Maruyama Fumito, Nakagawa Ichiro, Kuwae Asaomi, Abe Akio, Kunisawa Jun, Kiyono Hiroshi
  • Journal Title: International Immunology Volume: 32 Issue: 2 Pages: 133-141
  • DOI: 10.1093/intimm/dxz071
  • NAID: 120006888456
  • 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
• [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 Tomomi、Shibata Naoko、Kurashima Yosuke、Kiyono Hiroshi、Kurita-Ochiai Tomoko、Fujihashi Kohtaro
  • Journal Title: International Immunology Volume: - Issue: 8 Pages: 531-541
  • DOI: 10.1093/intimm/dxz029
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 (WAC) 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
  • Int'l Joint Research / Invited