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Development of liver fibrosis by monocyte-derived macrophages

Research Project

Project/Area Number 21K06877
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49010:Pathological biochemistry-related
Research InstitutionTokyo University of Pharmacy and Life Science

Principal Investigator

ASANO Kenichi  東京薬科大学, 生命科学部, 准教授 (10513400)

Co-Investigator(Kenkyū-buntansha) 濱田 理人  筑波大学, 医学医療系, 准教授 (20567630)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsMASH / 代謝障害関連脂肪肝炎 / EGR2 / マクロファージ / 単球 / 肝線維症 / 長鎖脂肪酸 / 分化 / 肝臓 / 線維化 / 非アルコール性脂肪肝炎 / Ym1 / 制御性単球
Outline of Research at the Start

本研究は「単球から分化したマクロファージが線維化の病態形成において何をしているのか」という問いに答えることを目指し、肝線維症準備期から進行期への転換における単球・マクロファージの役割を、Ym1という明確な指標を用いて解析する。具体的には、1)線維化進行期の肝臓に浸潤する単球からマクロファージへの分化機構と、2)単球由来マクロファージの肝線維症の病態形成における役割の解明を目指す。本研究の成果は、単球由来マクロファージによる線維化進展機構の解明に繋がるだけでなく、肝線維症の新たな治療標的同定に貢献できる可能性がある。

Outline of Final Research Achievements

In this study, we found a long chain saturated fatty acid-Egr2 pathway controls the progression of MASH in mice. The transcription factor Egr2 drives the differentiation of monocytes into hepatic lipid-associated macrophages (hLAMs) within MASH liver. Egr2-deficiency biases monocyte differentiation towards a macrophage subset resembling resident Kupffer cells, hampering hLAM formation. This shift suppressed the transition from benign steatosis to liver fibrosis, demonstrating the critical pro-fibrotic role played by hLAMs in MASH pathogenesis. Long chain saturated fatty acids that accumulate in MASH liver enhanced Egr2 expression in macrophages, a process counteracted by unsaturated fatty acids. Oral oleic acid administration promptly and effectively reduced hLAMs in MASH mice. In summary, our work highlights the therapeutic promise of targeting the saturated fatty acid-Egr2 axis in monocytes for MASH management.

Academic Significance and Societal Importance of the Research Achievements

本研究により、単球からマクロファージへの分化をコントロールする転写因子と環境因子が同定できた。Egr2によって誘導される単球由来マクロファージのサブセットが肝線維症の増悪に関与することを生体レベルで証明し、MASH進展における単球由来マクロファージの役割は何かという肝臓病学の課題に解答することができた。
オレイン酸を2週間経口投与することで、線維化マクロファージの割合を減少できることを示した。この研究成果は、単球―長鎖飽和脂肪酸―Egr2経路を標的とした肝線維症への介入療法開発に貢献できる。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • Research Products

    (14 results)

All 2024 2023 2022 2021

All Journal Article (8 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 8 results,  Open Access: 7 results) Presentation (2 results) Patent(Industrial Property Rights) (4 results)

  • [Journal Article] Egr2 drives the differentiation of Ly6Chi monocytes into fibrosis-promoting macrophages in metabolic dysfunction-associated steatohepatitis in mice.2024

    • Author(s)
      Ayaka Iwata, 他12名
    • Journal Title

      Communications Biology

      Volume: - Issue: 1

    • DOI

      10.1038/s42003-024-06357-5

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Synaptic pruning of murine adult-born neurons by microglia depends on phosphatidylserine2022

    • Author(s)
      Kurematsu Chihiro、Sawada Masato、Ohmuraya Masaki、他
    • Journal Title

      Journal of Experimental Medicine

      Volume: 219 Issue: 4

    • DOI

      10.1084/jem.20202304

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CD169+ macrophages in lymph node and spleen critically depend on dual RANK and LTbetaR signaling2022

    • Author(s)
      Camara Abdouramane、Lavanant Alice C.、Abe Jun、Desforges Henri Lee、Alexandre Yannick O.、Girardi Erika、Igamberdieva Zinaida、Asano Kenichi、Tanaka Masato、Hehlgans Thomas、Pfeffer Klaus、Pfeffer Sebastien、Mueller Scott N.、Stein Jens V.、Mueller Christopher G.
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 119 Issue: 3

    • DOI

      10.1073/pnas.2108540119

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CD169-positive macrophages enhance abscopal effect of radiofrequency ablation therapy in liver cancer2022

    • Author(s)
      Song Xiaojia、Li Na、Liu Yuan、Wang Zehua、Wang Tixiao、Tan Siyu、Li Chunyang、Qiu Chunhong、Gao Lifen、Asano Kenichi、Tanaka Masato、Liang Xiaohong、Liu Xinyong、Ma Chunhong
    • Journal Title

      Translational Oncology

      Volume: 15 Issue: 1 Pages: 101306-101306

    • DOI

      10.1016/j.tranon.2021.101306

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pathogenic roles and therapeutic potential of the CCL8-CCR8 axis in a murine model of IgG4-related sialadenitis2021

    • Author(s)
      Honda Fumika、Tsuboi Hiroto、Ono Yuko、Abe Saori、Takahashi Hiroyuki、Ito Kiyoaki、Yamada Kazunori、Kawano Mitsuhiro、Kondo Yuya、Asano Kenichi、Tanaka Masato、Malissen Marie、Malissen Bernard、Matsumoto Isao、Sumida Takayuki
    • Journal Title

      Arthritis Research & Therapy

      Volume: 23 Issue: 1 Pages: 214-214

    • DOI

      10.1186/s13075-021-02597-6

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Replication of Influenza A Virus in Secondary Lymphatic Tissue Contributes to Innate Immune Activation2021

    • Author(s)
      Friedrich Sarah-Kim、Schmitz Rosa、Bergerhausen Michael、Lang Judith、Duhan Vikas、Hardt Cornelia、Tenbusch Matthias、Prinz Marco、Asano Kenichi、Bhat Hilal、Hamdan Thamer A.、Lang Philipp Alexander、Lang Karl Sebastian
    • Journal Title

      Pathogens

      Volume: 10 Issue: 5 Pages: 622-622

    • DOI

      10.3390/pathogens10050622

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Deletion of Alox15 improves kidney dysfunction and inhibits fibrosis by increased PGD2 in the kidney2021

    • Author(s)
      Takahashi Naohiro、Kikuchi Hiroaki、Usui Ayaka、Furusho Taisuke、Fujimaru Takuya、Fujiki Tamami、Yanagi Tomoki、Matsuura Yoshiaki、Asano Kenichi、Yamamoto Kouhei、Ando Fumiaki、Susa Koichiro、Mandai Shintaro、Mori Takayasu、Rai Tatemitsu、Uchida Shinichi、Arita Makoto、Sohara Eisei
    • Journal Title

      Clinical and Experimental Nephrology

      Volume: 25 Issue: 5 Pages: 445-455

    • DOI

      10.1007/s10157-021-02021-y

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Immunoregulatory Monocyte Subset Promotes Metastasis Associated With Therapeutic Intervention for Primary Tumor2021

    • Author(s)
      Shibuya Takumi、Kamiyama Asami、Sawada Hirotaka、Kikuchi Kenta、Maruyama Mayu、Sawado Rie、Ikeda Naoki、Asano Kenichi、Kurotaki Daisuke、Tamura Tomohiko、Yoneda Atsuko、Imada Keisuke、Satoh Takashi、Akira Shizuo、Tanaka Masato、Yotsumoto Satoshi
    • Journal Title

      Frontiers in Immunology

      Volume: 12 Pages: 663115-663115

    • DOI

      10.3389/fimmu.2021.663115

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] EGR2 plays a pivotal role in the differentiation of Ly6Chi monocytes into fibrosis-promoting macrophages in non-alcoholic steatohepatitis.2024

    • Author(s)
      岩田彩花、田中正人、浅野謙一
    • Organizer
      第52回 日本免疫学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] EGR2は単球から線維化促進マクロファージへの 分化を促進し、NASHにおける肝線維症を増悪する2023

    • Author(s)
      岩田彩花、田中正人、浅野謙一
    • Organizer
      第96回 日本生化学会
    • Related Report
      2023 Annual Research Report
  • [Patent(Industrial Property Rights)] CCL8による免疫細胞の動員が関与する炎症を抑制するための組成物2021

    • Inventor(s)
      田中正人、浅野謙一
    • Industrial Property Rights Holder
      田中正人、浅野謙一
    • Industrial Property Rights Type
      特許
    • Filing Date
      2021
    • Related Report
      2021 Research-status Report
  • [Patent(Industrial Property Rights)] 多発性骨髄腫の処置のための医薬組成物2021

    • Inventor(s)
      田中正人、浅野謙一
    • Industrial Property Rights Holder
      田中正人、浅野謙一
    • Industrial Property Rights Type
      特許
    • Filing Date
      2021
    • Related Report
      2021 Research-status Report
  • [Patent(Industrial Property Rights)] がんの予防および/または治療のための医薬組成物2021

    • Inventor(s)
      田中正人、浅野謙一、池田直輝、四元聡志
    • Industrial Property Rights Holder
      田中正人、浅野謙一、池田直輝、四元聡志
    • Industrial Property Rights Type
      特許
    • Filing Date
      2021
    • Related Report
      2021 Research-status Report
  • [Patent(Industrial Property Rights)] がん転移抑制のための医薬組成物2021

    • Inventor(s)
      田中正人、浅野謙一、四元聡志、澁谷拓未、池田直輝
    • Industrial Property Rights Holder
      田中正人、浅野謙一、四元聡志、澁谷拓未、池田直輝
    • Industrial Property Rights Type
      特許
    • Filing Date
      2021
    • Related Report
      2021 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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