Elucidation of mechanisms underlying multi-organ cooperative regulation by analyzing immune cells migrated from gut to whole body and their functional molecules

• Project/Area Number: 16H05087
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Osaka Ohtani University
• Principal Investigator: Michio Tomura 大阪大谷大学, 薬学部, 教授 (30314321)
• Research Collaborator: KUSUMOTO yutaka ; MORIYA taiki ; ADACHI takahiro ; Ueda mizuki ; NISHII akiko
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2017: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2016: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: 腸管 / 免疫細胞移動 / パイエル板 / 骨髄 / 光変換蛍光タンパク質発現マウス / 腸内共生細菌叢 / 腸内共生細菌層 / B細胞 / 乳酸菌 / 臓器幹細胞移動 / 光変換蛍光タンパク質 / KIKGR / 細胞移動 / 腫瘍 / 臓器間細胞移動 / 腸内環境 / 無菌化 / KikGRマウス / 免疫細胞 / 脂肪

Outline of Final Research Achievements

The intestinal environment is thought to be involved in systemic diseases such as cancer, obesity and diabetes, however the mechanism is poorly understood. Therefore, in this study, we aimed to clarify the mechanism of multi-organ cooperation starting from the intestinal tract, focusing on immune cells migrated from intestinal tissue to multiple organs. We analyzed cells migrated from gut-related tissues to whole body by KikGR mice that can track cell movement between organs in normal food intake, high fat diet intake mice, and enteric commensal bacteria-free mice with antibiotics. Then, we clarified immune cell subsets and phenotypes that are migrated to the immune system. Furthermore, we found the mechanism that enteric tissue-derived cells stimulated by commensal bacteria migrate to the bone marrow and express function.

Academic Significance and Societal Importance of the Research Achievements

腸管から移行した細胞を明確に特定できる臓器間細胞動態評価系を用いることで、腸管内環境変化時の多臓器への免疫細胞動態を明らかにしたこと、さらに、腸管から骨髄に移行した細胞の機能的な役割は新しい概念である。これらは、腸管を起点とした移動した免疫細胞による多臓器連携の生体恒常性維持機構の理解に重要な知見であり学術的な意義は大きい。
また社会でも、食による共生細菌制御を介した腸管環境制御による全身性の疾患制御への注目が高まっており、食の改善、介入による免疫系を介した全身レベルの健康状態維持の重要性を示せたことの社会的な意義は大きい。

Research Products

• [Journal Article] Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10 (2019)
  • Author(s): Rojas OL, Probstel AK, Porfilio EA, Wang AA, Charabati M, Sun T, Lee DSW, Galicia G, Ramaglia V, Ward LA, Leung LYT, Najafi G, Khaleghi K, Garcillan B, Li A, Besla R, Naouar I, Cao EY, Chiaranunt P, Burrows K, Robinson HG, Allanach JR, Yam J, Luck H, Campbell DJ, Allman D, Brooks DG, Tomura M, (10名), Gommerman JL
  • Journal Title: Cell Volume: 176 Issue: 3 Pages: 610-624.e18
  • DOI: 10.1016/j.cell.2018.11.035
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Spatiotemporal Modeling of the Key Migratory Events During the Initiation of Adaptive Immunity (2019)
  • Author(s): Hayes Alan J.、Rane Sanket、Scales Hannah E.、Meehan Gavin R.、Benson Robert A.、Maroof Asher、Schroeder Juliane、Tomura Michio、Gozzard Neil、Yates Andrew J.、Garside Paul、Brewer James M.
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 598-598
  • DOI: 10.3389/fimmu.2019.00598
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional Phenotypic Diversity of Regulatory T Cells Remaining in Inflamed Skin (2019)
  • Author(s): Ikebuchi Ryoyo、Fujimoto Maika、Nakanishi Yasutaka、Okuyama Hiromi、Moriya Taiki、Kusumoto Yutaka、Tomura Michio
  • Journal Title: Frontiers in Immunology Volume: 10
  • DOI: 10.3389/fimmu.2019.01098
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] New Tools for Imaging of Immune Systems: Visualization of Cell Cycle, Cell Death, and Cell Movement by Using the Mice Lines Expressing Fucci, SCAT3.1, and Kaede and KikGR (2018)
  • Author(s): Tomura Michio
  • Journal Title: Methods Mol Bio Volume: 1763 Pages: 165-174
  • DOI: 10.1007/978-1-4939-7762-8_16
  • ISBN: 9781493977611, 9781493977628
• [Journal Article] Hepato‐entrained B220+ CD11c+ NK1.1+ cells regulate pre‐metastatic niche formation in the lung (2018)
  • Author(s): Hiratsuka Sachie、Tomita Takeshi、Mishima Taishi、Matsunaga Yuta、Omori Tsutomu、Ishibashi Sachie、Yamaguchi Satoshi、Hosogane Tsuyoshi、Watarai Hiroshi、Omori‐Miyake Miyuki、Yamamoto Tomoko、Shibata Noriyuki、Watanabe Akira、Aburatani Hiroyuki、Tomura Michio、High Katherine A、Maru Yoshiro
  • Journal Title: EMBO Molecular Medicine Volume: 10 Issue: 7
  • DOI: 10.15252/emmm.201708643
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression (2018)
  • Author(s): Calcinotto A、Brevi A、Chesi M、Ferrarese R、Garcia P L、Grioni M、Kumar S、Garbitt V M.、Sharik M E.、Henderson K J.、Tonon G、Tomura M、Miwa Y、Esplugues Enric、Flavell Richard A.、Huber Samuel、Canducci Filippo、Rajkumar Vincent S.、Bergsagel P. Leif、Bellone Matteo
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 4832-4832
  • DOI: 10.1038/s41467-018-07305-8
  • NAID: 120007128298
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Novel Cellular Pathway of Antigen Presentation and CD4 T Cell Activation in vivo (2018)
  • Author(s): Scales HE, Meehan GR, Hayes AJ, Benson RA, Watson E, Walters A, Tomura M, Maraskovsky E, Garside P, Baz Morelli A, Brewer JM
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 2684-2684
  • DOI: 10.3389/fimmu.2018.02684
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulatory T cells with superior immunosuppressive capacity emigrate from the inflamed colon to draining lymph nodes. (2018)
  • Author(s): Nakanishi Y, Ikebuchi R, Chtanova T, Kusumoto Y, Okuyama H, Moriya T, Honda T, Kabashima K, Watanabe T, Sakai Y, Tomura M.
  • Journal Title: Mucosal Immunol Volume: 11 Issue: 2 Pages: 437-448
  • DOI: 10.1038/mi.2017.64
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Colonic Tregs migrated from inflamed colon proliferate in draining lymph node. Simultaneous detection of cellular movement and proliferation (2018)
  • Author(s): OMURA Michio, UEDA Mizuki, IKEBUCHI Ryoyo, MORIYA Taiki, YASUDA Ippei, KUSUMOTO Yutaka
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] 大腸から所属リンパ節に移行した制御性 T 細胞の増殖 ―臓器間細胞移動と細胞周期の同時検出― (2018)
  • Author(s): 植田都月、西居亜希子、小林宏子、池渕良洋、 守屋大樹、安田一平、楠本 豊、戸村道夫
  • Organizer: 日本薬学会近畿支部第68回大会
• [Presentation] 戸村道夫、植田都月、池渕良洋、守屋大樹、安田一平、楠本 豊 (2018)
  • Author(s): 大腸から所属リンパ節に移行した制御性 T 細胞の増殖 ―臓器間細胞移動と細胞周期の同時検出―
  • Organizer: 日本分子生物学会第41回年会
• [Presentation] Regulatory T cell movement and heterogeneity in inflamed skin and colon (2018)
  • Author(s): Michio Tomura, Ryoyo Ikebuchi, Yasutaka Nakanishi, Taiki Moriya, Mizuki Ueda
  • Organizer: 第11回寄生虫感染免疫研究会
• [Presentation] カエデマウスを用いた、免疫 細胞の臓器間移動情報に基づく免疫系の理解 (2017)
  • Author(s): 戸村 道夫
  • Organizer: 第7回オルソオルガノジェネシス検討会
• [Presentation] Specific features of Tregs migrated from skin and colon to the draining lymph node in the steady state and under inflammation (2017)
  • Author(s): Michio Tomura
  • Organizer: ICIS 2017- International Conference on Information Systems
  • Int'l Joint Research / Invited
• [Book] ラボ必携 フローサイトメトリーQ&A 正しいデータを出すための100箇条 (2017)
  • Author(s): 戸村道夫 他59名、戸村道夫／編
  • Total Pages: 313
  • Publisher: 羊土社
  • ISBN: 9784758122351