Role of innate lymphoid cells in adipose tissue homeostasis

2018 Fiscal Year Annual Research Report

• Project/Area Number: 16H02631
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: 小安 重夫 国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (90153684)
• Co-Investigator(Kenkyū-buntansha): 茂呂 和世 国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (90468489)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 肥満 / 自然リンパ球 / 脂肪組織炎症

Outline of Annual Research Achievements

昨年までに、高脂肪食負荷を与えた際の体重増加に、小腸粘膜固有層由来の2型自然リンパ球（SI-ILC2）が関与し、SI-ILC2が腸間膜由来のILC2（WAT-ILC2）と異なる性質を持つことを明らかにしてきた。SI-ILC2とWAT-ILC2に機能的差異を検討するために、それぞれの細胞を用いてRNASeq解析を行い、肥満の誘導に関わる遺伝子の探索を行った。昨年はWAT-ILC2に比較してSI-ILC2において発現が10倍以上高かったIL-2の重要性を明らかにしたが、それ以外にも、リポタンパク質の分解酵素を抑制するAngptl4やタイトジャンクションを構成するTjp1などが候補に挙がったが、決定的な証拠を得ることはできていない。
WAT-ILC2がなぜ肥満を誘導しないかという点に関して考察した。過去にWAT-ILC2が褐色脂肪細胞の誘導を介してむしろ肥満の抑制に関わるという報告があることから、WAT-ILC2の移植の際には肥満の誘導活性と抑制活性が拮抗している可能性が考えられた。そこでWAT-ILC2と脂肪細胞分化の関係を検討するためにトランスウエルを用いた培養系で前脂肪細胞から脂肪細胞への分化に与えるILC2の影響を詳細に解析したところ、活性化したILC2が脂肪細胞の分化を抑制することが明らかになった。興味深いことに抑制活性は脂肪細胞の分化の途中にILC2を共存させた場合のみ観察され、分化前や分化後に共存させても影響は見られなかった。一方、WAT-ILC2の培養上清も前脂肪細胞から脂肪細胞への分化を抑制し、コラーゲン発現を上昇させるなど繊維化を誘導することが明らかになった。これらの活性に関与する分子をRNASeq解析やプロテオミクス解析によって検討しているが同定には至っていない。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] University of Bergen(ノルウェー)
  • Country Name: NORWAY
  • Counterpart Institution: University of Bergen
• [Int'l Joint Research] Cornell University/Washington University/University of California San Francisco(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Cornell University/Washington University/University of California San Francisco
• [Int'l Joint Research] MRC Laboratory of Molecular Biology/University of Oxford(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: MRC Laboratory of Molecular Biology/University of Oxford
• [Int'l Joint Research] CIML/Institut Pasteur(フランス)
  • Country Name: FRANCE
  • Counterpart Institution: CIML/Institut Pasteur
• [Int'l Joint Research] Berlin Institute of Health(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: Berlin Institute of Health
• [Int'l Joint Research]
  • # of Other Countries: 1
• [Journal Article] Innate lymphoid cells in the induction of obesity. (2019)
  • Author(s): Sasaki, T., Moro, K., Kubota, T., Kubota, N., Kato, T., Ohno, H., Nakae, S., Saito, H. and Koyasu, S.
  • Journal Title: Cell Reports Volume: 印刷中 Pages: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Hide and seek: Plasticity of innate lymphoid cells in cancer. (2019)
  • Author(s): Bald, T., Wagner, M., Gao, Y., Koyasu, S. and Smyth, M. J.
  • Journal Title: Seminars in Immunology Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1016/j.smim.2019.04.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cancer immunoediting by innate lymphoid cells. (2019)
  • Author(s): Wagner, M. and Koyasu, S.
  • Journal Title: Trends in Immunology Volume: 40 Pages: 415-430
  • DOI: 10.1016/j.it.2019.03.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms (2018)
  • Author(s): Kabata, H., Moro, K. and Koyasu, S.
  • Journal Title: Immunological Reviews Volume: 286 Pages: 37-52
  • DOI: 10.1111/imr.12706
  • Peer Reviewed
• [Journal Article] Innate lymphoid cells: 10 years on. (2018)
  • Author(s): Vivier, E., Artis, D., Colonna, M., Diefenbach, A., Di Santo, J. P., Eberl, G., Koyasu, S., Locksley, R. M., McKenzie, A. N. J., Mebius, R. E., Powrie, F. and Spits, H.
  • Journal Title: Cell Volume: 174 Pages: 1054-1066
  • DOI: 10.1016/j.cell.2018.07.017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Peripheral PDGFRα+gp38+ mesenchymal cells support the differentiation of fetal liver-derived ILC2. (2018)
  • Author(s): Koga, S., Hozumi, K., Hirano, K., Yazawa, M., Terooatea, T., Minoda, A., Nagasawa, T., Koyasu, S. and Moro, K.
  • Journal Title: Journal of Experimental Medicine Volume: 215 Pages: 1609-1626
  • DOI: 10.1084/jem.20172310
  • Peer Reviewed
• [Presentation] Tolerance break by class switch recombination for auto-antibody production. (2018)
  • Author(s): Shigeo Koyasu
  • Organizer: The 7th FIMSA Congress
  • Int'l Joint Research / Invited
• [Presentation] Environmental factors controlling the peripheral differentiation of ILC2. (2018)
  • Author(s): Shigeo Koyasu
  • Organizer: The 32nd Collegium Internationale Allergologicum
  • Int'l Joint Research
• [Presentation] Innate lymphoid cells, a new type of lymphocytes without antigen receptors. (2018)
  • Author(s): Shigeo Koyasu
  • Organizer: Interdiscipilinary Science Conference
  • Int'l Joint Research / Invited
• [Presentation] Involvement of innate lymphoid cells in the iduction of diet-induced obesity. (2018)
  • Author(s): Takaharu Sasaki, Kazuyo Moro, Tetsuya Kubota, Naoto Kubota, Hiroshi Ohno, Shigeo Koyasu
  • Organizer: The 3rd International Conference on Innate Lymphoid Cells
  • Int'l Joint Research
• [Presentation] Mechanisms for the regulation of adipose tissue expansion and remodeling by group 2 innate lymphoid cells. (2018)
  • Author(s): Kafi Nequan Ealey, Shigeo Koyasu, Yibo Wu, Kazuyo Moro
  • Organizer: The 3rd International Conference on Innate Lymphoid Cells
  • Int'l Joint Research
• [Presentation] Group 2 innate lymphoid cells regulate susceptibility to allergic lung inflammation via an innate amplification circuit. (2018)
  • Author(s): Yasutaka Motomura, Shigeo Koyasu, Kazuyo Moro
  • Organizer: The 3rd International Conference on Innate Lymphoid Cells
  • Int'l Joint Research
• [Presentation] Group 2 innate lymphoid cells exacerbate severe amebic liver abscess by IFN-gamma independent manner in mice. (2018)
  • Author(s): Risa Nakamura, Sharmina Deloer, Masachika Senba, Mihoko Kikuchi, Shigeo Koyasu, Kazuyo Moro, Shinjiro Hamano
  • Organizer: The 3rd International Conference on Innate Lymphoid Cells
  • Int'l Joint Research