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Development of novel therapeutic strategy against neurodegenerative diseases by modulation of monocyte-lineage cell

Research Project

Project/Area Number 18K07531
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52020:Neurology-related
Research InstitutionYokohama City University

Principal Investigator

TAKEUCHI Hideyuki  横浜市立大学, 医学部, 准教授 (30362213)

Co-Investigator(Kenkyū-buntansha) 土井 宏  横浜市立大学, 医学部, 准教授 (10326035)
田中 章景  横浜市立大学, 医学研究科, 教授 (30378012)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords単球系細胞 / ミクログリア / マクロファージ / アストロサイト / 神経炎症 / IL-19 / 神経変性疾患
Outline of Final Research Achievements

IL-19 acts as a negative-feedback regulator to limit proinflammatory response of macrophages/microglia. We showed that IL-19 deficiency aggravates EAE and IL-19-treatment significantly abrogated it. IL-19 suppresses MS pathogenesis by inhibiting macrophage antigen presentation. IL-19-deficient SOD1 Tg mice exhibited significant improvement of motor function accompanied by upregulating microglial TNF-α and subsequent astrocytic GDNF, indicating that inhibition of IL-19 signaling may alleviate ALS symptoms. Then, we generated CX3CR1/CCR2-reporter SOD1 Tg mice that enables distinction between microglia and CNS infiltrating macrophage. We found that microglia and neurons partially expressed CCR2, but not astrocytes, associated with an increase in CNS infiltrating CCR2+ macrophage as disease progression, suggesting that macrophage CNS infiltration leads to CNS environmental deterioration due to toxic conversion of microglia and neurons.

Academic Significance and Societal Importance of the Research Achievements

単球系細胞のネガティブフィードバック因子であるIL-19が、神経免疫疾患や神経変性疾患といった病態の違いに応じて、神経保護作用・神経障害作用の二面性を示しうることを明らかにした。また、ALSモデルマウスの病勢進行に伴ったCCR2陽性単球の中枢神経浸潤の増加と、ミクログリアや神経細胞におけるCCR2の発現誘導が、神経炎症の悪循環を惹起し、ALSの病態形成の一機序を担っている可能性を示した。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (8 results)

All 2021 2020 2019 2018

All Journal Article (4 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (4 results) (of which Invited: 3 results)

  • [Journal Article] Interleukin-19 Abrogates Experimental Autoimmune Encephalomyelitis by Attenuating Antigen-Presenting Cell Activation2021

    • Author(s)
      Horiuchi Hiroshi、Parajuli Bijay、Komiya Hiroyasu、Ogawa Yuki、Jin Shijie、Takahashi Keita、Azuma Yasu-Taka、Tanaka Fumiaki、Suzumura Akio、Takeuchi Hideyuki
    • Journal Title

      Frontiers in Immunology

      Volume: 12 Pages: 615465-615465

    • DOI

      10.3389/fimmu.2021.615898

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Ablation of interleukin-19 improves motor function in a mouse model of amyotrophic lateral sclerosis2021

    • Author(s)
      Komiya Hiroyasu、Takeuchi Hideyuki、Ogawa Yuki、Suzuki Kosuke、Ogasawara Akihiro、Takahashi Keita、Azuma Yasu-Taka、Doi Hiroshi、Tanaka Fumiaki
    • Journal Title

      Molecular Brain

      Volume: 14 Issue: 1 Pages: 74-74

    • DOI

      10.1186/s13041-021-00785-8

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CCR2 is localized in microglia and neurons, as well as infiltrating monocytes, in the lumbar spinal cord of ALS mice.2020

    • Author(s)
      Komiya H, Takeuchi H (責任著者), Ogawa Y, Hatooka Y, Takahashi K, Katsumoto A, Kubota S, Nakamura H, Kunii M, Tada M, Doi H, Tanaka F
    • Journal Title

      Molecular Brain

      Volume: 13 Issue: 1 Pages: 64-64

    • DOI

      10.1186/s13041-020-00607-3

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Tau Pathology in Chronic Traumatic Encephalopathy and Alzheimer's Disease: Similarities and Differences.2019

    • Author(s)
      Katsumoto A, Takeuchi H (責任著者), Tanaka F
    • Journal Title

      Frontiers in Neurology

      Volume: 10 Pages: 980-980

    • DOI

      10.3389/fneur.2019.00980

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] シンポジウム「神経免疫と認知症・精神疾患」・神経免疫と精神・神経疾患2020

    • Author(s)
      竹内 英之
    • Organizer
      第32回日本神経免疫学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] シンポジウム「神経免疫疾患の病態解明への多面的アプローチ」・グリア細胞からのアプローチ.2019

    • Author(s)
      竹内英之
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Gap junction/hemichannel blockers ameliorate a mouse model of neuropathic pain.2018

    • Author(s)
      竹内英之
    • Organizer
      第59回日本神経学会学術大会
    • Related Report
      2018 Research-status Report
  • [Presentation] グリアを標的とした神経疾患の治療法開発2018

    • Author(s)
      竹内英之
    • Organizer
      第61回日本神経化学会大会
    • Related Report
      2018 Research-status Report
    • Invited

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Published: 2018-04-23   Modified: 2022-01-27  

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