Elucidation of the mechanisms by which paired immune receptors regulate hepatic ischemia reperfusion injury

• Project/Area Number: 20K17000
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Juntendo University
• Principal Investigator: Yin Enzhi 順天堂大学, 大学院医学研究科, 非常勤助教 (70844786)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 虚血再灌流障害 / 肝臓 / ペア型免疫受容体 / 肝臓虚血再灌流障害

Outline of Research at the Start

肝臓手術の成功には虚血再灌流障害の制御が不可欠である。常在性クッパー細胞と局所に動員される単球/マクロファージや好中球が肝臓虚血再灌流障害の制御に重要な役割を担うが、その制御メカニズムの解明は不十分である。ペア型免疫受容体は、細胞外領域に相同性の高い構造を持ち、免疫細胞の活性化を促進あるいは抑制する。
本研究は好中球や単球/マクロファージに発現するペア型免疫受容体に着目して、肝臓虚血再還流障害の分子機序を解明することを目指す。

Outline of Final Research Achievements

We used murine models of hepatic ischemia reperfusion injury in wild-type, an inhibitory receptor-deficient, and an activating receptor-deficient mice. Loss of an inhibitory receptor tested did not significantly influence hepatic ischemia reperfusion injury. In contrast, loss of an activating receptor tested reduced the numbers of neutrophils recruited to and the levels of inflammatory cytokines in the liver following ischemia-reperfusion, thereby alleviating the hepatic damage. Thus, the deficiency of an activating receptor tested, specifically expressed in neutrophils, exacerbated hepatic ischemia reperfusion injury.

Academic Significance and Societal Importance of the Research Achievements

本研究により、ペア型免疫受容体ファミリーに属する特定の活性化型受容体が肝臓虚血再灌流障害を悪化させる働きをもつことが明らかになった。好中球に特異的に発現する活性化型受容体が虚血再灌流した肝臓への好中球集積を促進し、炎症を誘導し、肝障害を悪化させると考えられた。これらの研究成果は、肝臓虚血再灌流障害の病態機序の解明と予防・治療法の開発につながり、学術的意義と社会的意義を有すると考えられる。

Research Products

• [Journal Article] Analysis of therapeutic potential of monocytic myeloid-derived suppressor cells in cardiac allotransplantation. (2021)
  • Author(s): Keiichi Fujimoto, Koichiro Uchida, EnzhiYin, Jun Zhu, Yuko Kojima, Masateru Uchiyama, Yasuto Yamamoto, Hisashi Bashuda, Ryu Matsumoto, Koji Tokushige, Masaki Harada, Takenori Inomata, Jiro Kitaura, Akira Murakami, Ko Okumura, Kazuyoshi Takeda.
  • Journal Title: Transplant Immunology Volume: 67 Pages: 101405-101405
  • DOI: 10.1016/j.trim.2021.101405
  • Peer Reviewed / Open Access
• [Journal Article] Anti-CD321 antibody immunotherapy protects liver against ischemia and reperfusion-induced injury. (2021)
  • Author(s): Enzhi Yin, Takeshi Fukuhara, Kazuyoshi Takeda, Yuko Kojima, Kyoko Fukuhara, Kenichi Ikejima, Hisashi Bashuda, Jiro Kitaura, Hideo Yagita, Ko Okumura, Koichiro Uchida
  • Journal Title: Scientific Reports Volume: 6322 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41598-021-85001-2
  • Peer Reviewed / Open Access
• [Presentation] CD321 mAb（90G4）protects liver via inhibiting neutrophil infiltration in murine hepatic ischemia reperfusion model. (2020)
  • Author(s): 内田浩一郎, 殷 恩智, 場集田 寿, 竹田和由, 奥村 康.
  • Organizer: 第120回日本外科学会定期学術集会