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Symmetrical Gateway Reflex: Mechanism of Symmetrical Gateway Reflex

Research Project

Project/Area Number 21K07062
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49070:Immunology-related
Research InstitutionNational Institute for Physiological Sciences

Principal Investigator

Hasebe Rie  生理学研究所, 生体機能調節研究領域, 特任准教授 (70431335)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2023: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords多発性左右対称性(遠隔)炎症 / 神経-免疫連関 / ゲートウェイ反射 / 関節炎 / 関節リウマチ / 左右対称性(遠隔)炎症 / IL-6アンプ / 神経回路 / 左右対称性炎症
Outline of Research at the Start

関節リウマチなどの炎症性疾患では左右対称性の病変が起こる。その原因の一つとして神経回路の関連が示唆されているが、左右対称性炎症を誘導する神経回路や炎症に関連する分子機構についてはほとんど解明が進んでいない。申請者らは、左右対称性関節炎モデルマウスにおいて、ATPを介した感覚神経回路の活性化が左右対称性炎症を誘導することを明らかにした。本研究では同神経回路の特異マーカーを同定し、その機能を明らかにすることにより、左右対称性炎症の病態発生の分子機構を解明する。また、関節局所における感覚神経回路の活性化を制御することにより、左右対称性炎症性疾患の治療法開発へとつなげる。

Outline of Final Research Achievements

Multiple symmetrical inflammations in remote areas are common in inflammatory diseases including rheumatoid arthritis (RA). We have identified “Remote Inflammation Gateway Reflex” as a molecular mechanism of the remote inflammation by using two arthritis models. We found that an ATP-sensory-interneuron crosstalk induced secretion of ATP in remote joints followed by the IL-6 amplifier activation to develop arthritis. Although we have identified proenkephalin (PENK) as a marker of the interneurons, it is widely expressed in the spinal cord. To identify more specific functional markers, we performed single-cell RNAseq analysis, and extracted candidate genes X and Y. Activation of Penk or gene X-positive neurons in L5 spinal cord by chemogenetics induced the characterization of the Remote Inflammation Gateway Reflex, including activation of sensory neurons, increased ATP synthase expression, activation of IL-6 amplifier, and MHC class II+ cell proliferation in the synovium.

Academic Significance and Societal Importance of the Research Achievements

ゲートウェイ反射は、私たちの研究グループが発見した神経-免疫連関による新規の炎症病態調節機構である。そのうち遠隔炎症ゲートウェイ反射は、関節リウマチや乾癬など複数の炎症性疾患でみられる多発性炎症病態を説明しうる現象である。遠隔炎症ゲートウェイ反射を調節する神経ネットワークを理解することにより、末梢感覚神経-脊髄介在神経を介した神経-免疫連関の新たな概念を提唱できる。また、本研究で発見した神経細胞の機能マーカー分子を用いて、神経回路を制御することにより、炎症性疾患の新規治療法開発へとつながる可能性がある。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (38 results)

All 2024 2023 2022 2021 Other

All Journal Article (15 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 14 results,  Open Access: 12 results) Presentation (21 results) (of which Int'l Joint Research: 2 results) Remarks (2 results)

  • [Journal Article] Gateway reflexes describe novel neuro-immune communications that establish immune cell gateways at specific vessels2023

    • Author(s)
      Tanaka Hiroki、Hasebe Rie、Murakami Kaoru、Sugawara Toshiki、Yamasaki Takeshi、Murakami Masaaki
    • Journal Title

      Bioelectronic Medicine

      Volume: 9 Issue: 1 Pages: 24-24

    • DOI

      10.1186/s42234-023-00126-1

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in miniature dachshunds2023

    • Author(s)
      Teoh Yong Bin、Jiang Jing-Jing、Yamasaki Takeshi、Nagata Noriyuki、Sugawara Toshiki、Hasebe Rie、Ohta Hiroshi、Sasaki Noboru、Yokoyama Nozomu、Nakamura Kensuke、Kagawa Yumiko、Takiguchi Mitsuyoshi、Murakami Masaaki
    • Journal Title

      Frontiers in Veterinary Science

      Volume: 10 Pages: 1192888-1192888

    • DOI

      10.3389/fvets.2023.1192888

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] GM-CSF Promotes the Survival of Peripheral-Derived Myeloid Cells in the Central Nervous System for Pain-Induced Relapse of Neuroinflammation2023

    • Author(s)
      Matsuyama Shiina、Yamamoto Reiji、Murakami Kaoru、Takahashi Nobuhiko、Nishi Rieko、Ishii Asuka、Nio Kobayashi Junko、Abe Nobuya、Tanaka Kumiko、Jiang Jing Jing、Kawamoto Tadafumi、Iwanaga Toshihiko、Shinohara Yuta、(4名省略)、Kubota Shimpei I、(4名省略)、Murakami Masaaki
    • Journal Title

      The Journal of Immunology

      Volume: 211 Issue: 1 Pages: 34-42

    • DOI

      10.4049/jimmunol.2200567

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] In situ Microinflammation Detection Using Gold Nanoclusters and a Tissue-clearing Method2023

    • Author(s)
      Naim Fayrouz、Hasebe Rie、Hojyo Shintaro、Shichibu Yukatsu、Ishii Asuka、Tanaka Yuki、Tainaka Kazuki、Kubota Shimpei、Konishi Katsuaki、Murakami Masaaki
    • Journal Title

      BIO-PROTOCOL

      Volume: 13 Issue: 7 Pages: 7-7

    • DOI

      10.21769/bioprotoc.4644

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A point mutation in GPI-attachment signal peptide accelerates the development of prion disease2023

    • Author(s)
      Kobayashi Atsushi、Hirata Tetsuya、Shimazaki Taishi、Munesue Yoshiko、Aoshima Keisuke、Kimura Takashi、Nio-Kobayashi Junko、Hasebe Rie、Takeuchi Atsuko、Matsuura Yuichi、Kusumi Satoshi、Koga Daisuke、Iwasaki Yasushi、Kinoshita Taroh、Mohri Shirou、Kitamoto Tetsuyuki
    • Journal Title

      Acta Neuropathologica

      Volume: 145 Issue: 5 Pages: 637-650

    • DOI

      10.1007/s00401-023-02553-5

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Zoobiquity experiments show the importance of the local MMP9-plasminogen axis in inflammatory bowel diseases in both dogs and patients.2023

    • Author(s)
      Takeshi Yamasaki, Noriyuki Nagata, Toru Atsumi, Rie Hasebe, Yuki Tanaka, Izuru Ohki, Shimpei Kubota, Yuta Shinohara, Yong Bin Teoh, Nozomu Yokoyama, Noboru Sasaki, Kensuke Nakamura, Hiroshi Ohta, Takehiko Katsurada, Yoshihiro Matsuno, Shintaro Hojyo, Shigeru Hashimoto, Mitsuyoshi Takiguchi, Masaaki Murakami.
    • Journal Title

      International immunology

      Volume: - Issue: 7 Pages: 313-326

    • DOI

      10.1093/intimm/dxad006

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dupuytren's contracture-associated SNPs increase SFRP4 expression in nonimmune cells including fibroblasts to enhance inflammation development.2023

    • Author(s)
      Hiroaki Kida, Jing-Jing Jiang, Yuichiro Matsui, Ikuko Takahashi, Rie Hasebe, Daisuke Kawamura, Takeshi Endo, Hiroki Shibayama, Makoto Kondoh, Yasuhiko Nishio, Kinya Nishida, Yoshihiro Matsuno, Tsukasa Oikawa, Shimpei Kubota, Shintaro Hojyo, Norimasa Iwasaki, Shigeru Hashimoto, Yuki Tanaka, Masaaki Murakami.
    • Journal Title

      International immunology

      Volume: -

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cytokine and chemokine multiplex analysis-based exploration for potential treatment and prognostic prediction in large-vessel vasculitis: A preliminary observational study2022

    • Author(s)
      Abe Nobuya、Kono Michihiro、Kono Michihito、Katsuyama Takayuki、Ohmura Kazumasa、Sato Taiki、Karino Kohei、Fujieda Yuichiro、Kato Masaru、Hasebe Rie、Murakami Masaaki、Atsumi Tatsuya
    • Journal Title

      Frontiers in Immunology

      Volume: 13 Pages: 1066916-1066916

    • DOI

      10.3389/fimmu.2022.1066916

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Pathogenic neuropsychiatric effect of stress-induced microglial interleukin 12/23 axis in systemic lupus erythematosus2022

    • Author(s)
      Abe Nobuya、Tarumi Masato、Fujieda Yuichiro、Takahashi Nobuhiko、Karino Kohei、Uchida Mona、Kono Michihito、Tanaka Yuki、Hasebe Rie、Kato Masaru、Amengual Olga、Arinuma Yoshiyuki、Oku Kenji、Sato Wakiro、Tha Khin Khin、Yamasaki Miwako、Watanabe Masahiko、Atsumi Tatsuya、Murakami Masaaki
    • Journal Title

      Annals of the Rheumatic Diseases

      Volume: 81 Issue: 11 Pages: 1564-1575

    • DOI

      10.1136/ard-2022-222566

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ATP spreads inflammation to other limbs through crosstalk between sensory neurons and interneurons2022

    • Author(s)
      Hasebe, R., K. Murakami, M. Harada, N. Halaka, H. Nakagawa, F. Kawano, Y. Ohira, T. Kawamoto, F.E. Yull, T.S. Blackwell, J. Nio-Kobayashi, T. Iwanaga, M. Watanabe, N. Watanabe, H. Hotta, T. Yamashita, D. Kamimura, Y. Tanaka, and M. Murakami
    • Journal Title

      J. Exp. Med.

      Volume: 219 (6) Issue: 6

    • DOI

      10.1084/jem.20212019

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] BBBにおける免疫細胞の侵入口形成機構, ゲートウェイ反射について.2022

    • Author(s)
      西 李依子, 村上 薫, 長谷部 理絵, 村上 正晃
    • Journal Title

      Clinical Neuroscience

      Volume: 40(12) Pages: 1544-1548

    • Related Report
      2022 Research-status Report
  • [Journal Article] Gateway Reflex and Mechanotransduction2021

    • Author(s)
      Matsuyama S, Tanaka Y, Hasebe R, Hojyo S, Murakami M.
    • Journal Title

      Front Immunol.

      Volume: 12 Pages: 780451-780451

    • DOI

      10.3389/fimmu.2021.780451

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sjogren's syndrome-associated SNPs increase GTF2I expression in salivary gland cells to enhance inflammation development.2021

    • Author(s)
      Shimoyama S, Nakagawa I, Jiang JJ, Matsumoto I, Chiorini JA, Hasegawa Y, Ohara O, Hasebe R, Ota M, Uchida M, Kamimura D, Hojyo S, Tanaka Y, Atsumi T, Murakami M.
    • Journal Title

      Int Immunol.

      Volume: 33 Issue: 8 Pages: 423-434

    • DOI

      10.1093/intimm/dxab025

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Gateway reflexes, neuronal circuits that regulate the gateways for autoreactive T cells in organs that have blood barriers.2021

    • Author(s)
      Uchida M, Yamamoto R, Matsuyama S, Murakami K, Hasebe R, Hojyo S, Tanaka Y, Murakami M.
    • Journal Title

      Int Immunol.

      Volume: dxab022 Issue: 2 Pages: 59-65

    • DOI

      10.1093/intimm/dxab022

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rhodobacter azotoformans LPS (RAP99-LPS) Is a TLR4 Agonist That Inhibits Lung Metastasis and Enhances TLR3-Mediated Chemokine Expression.2021

    • Author(s)
      Murakami K, Kamimura D, Hasebe R, Uchida M, Abe N, Yamamoto R, Jiang JJ, Hidaka Y, Nakanishi Y, Fujita S, Toda Y, Toda N, Tanaka H, Akira S, Tanaka Y, Murakami M.
    • Journal Title

      Front Immunol.

      Volume: 12 Pages: 675909-675909

    • DOI

      10.3389/fimmu.2021.675909

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] The Gateway Reflex: a novel neuro-immune mechanism regulating tissue specific inflammatory diseases2024

    • Author(s)
      Rie Hasebe, Kaoru Murakami, Takeshi Yamasaki, Masaaki Murakami
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in Miniature Dachshunds2024

    • Author(s)
      Yong Bin Teoh, Jing-Jing Jiang, Takeshi Yamasaki, Noriyuki Nagata, Toshiki Sugawara, Rie Hasebe, 4 authors, Mitsuyoshi Takiguchi, and Masaaki Murakami
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Zoobiquity experiments show the importance of the local MMP9-plasminogen axis in inflammatory bowel diseases in both dogs and patients.2023

    • Author(s)
      Takeshi Yamasaki, Noriyuki Nagata, Toru Atsumi, Rie Hasebe, 13 authors, Mitsuyoshi Takiguchi, Masaaki Murakami.
    • Organizer
      JSICR/MMCB2023合同シンポジウム
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 遠隔炎症ゲートウェイ反射:ATPを介した感覚神経-介在神経クロストークによる遠隔部位での左右対称性関節炎誘導機構.2023

    • Author(s)
      長谷部 理絵, 村上 薫, 田中 勇希, 村上 正晃.
    • Organizer
      第46回日本神経科学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 遠隔炎症ゲートウェイ反射:ATP-感覚神経-介在神経のクロストークによる遠隔部位での左右対称性炎症の誘導機構.2023

    • Author(s)
      長谷部 理絵, 村上 薫, 北條慎太郎, 田中 勇希, 村上 正晃.
    • Organizer
      第128回 日本解剖学会総会・全国学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] 遠隔炎症ゲートウェイ反射:感覚神経-脊髄介在神経回路とATPによる遠隔部位での炎症誘導.2022

    • Author(s)
      長谷部 理絵, 村上 薫, 北條慎太郎, 田中 勇希, 村上 正晃.
    • Organizer
      第7回日本骨免疫学会
    • Related Report
      2022 Research-status Report
  • [Presentation] 遠隔炎症ゲートウェイ反射:局所の炎症反応で生じるATPは感覚神経-脊髄介在神経回路を活性化し、遠隔部位での炎症を誘導する.2022

    • Author(s)
      長谷部 理絵, 村上 薫, 北條 慎太郎, 田中 勇希, 村上 正晃.
    • Organizer
      量子生命化学会 第4回大会
    • Related Report
      2022 Research-status Report
  • [Presentation] ストレス依存性の内側前頭前野でのミクログリア内IL-12/23経路は神経ループスに関連する.2022

    • Author(s)
      山﨑 剛士, 阿部 靖矢, 田中 勇希, 長谷部 理絵, 久保田 晋平, 橋本 茂, 北條 慎太郎, 上村 大輔, 村上 正晃.
    • Organizer
      第7回日本骨免疫学会
    • Related Report
      2022 Research-status Report
  • [Presentation] Pathogenic neuropsychiatric effect of stress-induced microglial interleukin 12/23 axis in SLE2022

    • Author(s)
      Yuki Tanaka, Nobuya Abe, Masato Tarumi, Rie Hasebe, Tatsuya Atsumi, Masaaki Murakami
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] ゲートウェイ反射による組織特異的な炎症性疾患の誘導機構2022

    • Author(s)
      久保田晋平、長谷部理絵、村上薫、田中勇希、村上正晃
    • Organizer
      第102回北海道医学大会病理分科会・第55回北海道病理談話会
    • Related Report
      2022 Research-status Report
  • [Presentation] ATPによる感覚神経-介在神経回路の活性化は遠隔部位での炎症反応を誘導する2021

    • Author(s)
      長谷部 理絵, 田中 勇希, 北條 慎太郎, 村上 正晃
    • Organizer
      第85回日本インターフェロン・サイトカイン学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 紅色非硫黄細菌LPSによる免疫活性化作用2021

    • Author(s)
      村上薫、阿部靖矢、山本励志、Jing-Jing Jiang, 長谷部理絵、上村大輔、田中勇希、村上正晃
    • Organizer
      第85回日本インターフェロン・サイトカイン学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] ストレス依存性SARS-CoV-2感染マウスモデルを用いたCOVID-19病態機序の解明2021

    • Author(s)
      北條慎太郎, 田中くみ子, 田中勇希, 長谷部理絵, 内田萌菜, 村上正晃
    • Organizer
      第42回日本炎症・再生医学会
    • Related Report
      2021 Research-status Report
  • [Presentation] 慢性ストレスは神経ループスにおいてミクログリアのIL-12/23経路を活性化し、内側前頭前野の機能障害を誘導する2021

    • Author(s)
      長谷部 理絵, 阿部 靖矢, 北條 慎太郎, 田中 勇希, 上村 大輔, 村上 正晃
    • Organizer
      一般社団法人量子生命科学第3回大会
    • Related Report
      2021 Research-status Report
  • [Presentation] Metabolite NTP1 suppresses CNS inflammation via pathogenic T cell activation,2021

    • Author(s)
      Yuki Tanaka, Rie Hasebe, Shintaro Hojyo, Madoka Higuchi, Daisuke Kamimura, and Masaaki Murakami
    • Organizer
      第16回生命医科学研究所ネットワーク国際シンポジウム
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Rhodobacter azotoformans LPS is a TLR4 agonist that suppresses cytokine storm and enhances TLR3-mediated chemokine expression2021

    • Author(s)
      Kaoru Murakami, Daisuke Kamimura, Rie Hasebe, Mona Uchida, Nobuya Abe, Reiji Yamamoto, Jing-Jing Jiang, Hiroki Tanaka, Shizuo Akira, Yuki Tanaka, Masaaki Murakami
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Establishment of a severe COVID-19 model in mice with stress2021

    • Author(s)
      Shintaro Hojyo, Rie Hasebe, Kumiko Tanaka, Yuki Tanaka, Mona Uchida, Masaaki Murakami
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Roles of a metabolite during EAE development2021

    • Author(s)
      Yuki Tanaka, Rie Hasebe, Shintaro Hojyo, Madoka Higuchi, Daisuke Kamimura, and Masaaki Murakami
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Inflammation spreads to other limbs through an ATP-mediated sensory-interneuron network2021

    • Author(s)
      Rie Hasebe, Yuki Tanaka, Shintaro Hojyo, Daisuke Kamimura, Masaaki Murakami
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Chronic stress-induced microglial interleukin-12/23 axis and medial prefrontal cortex impairment in neuropsychiatric lupus2021

    • Author(s)
      Nobuya Abe, Yuichiro Fujieda, Kenji Oku, Nobuhiko Takahashi, Kohei Karino, Mona Uchida, Michihito Kono, Yuki Tanaka, Rie Hasebe, Masaru Kato, Tatsuya Atsumi, Masaaki Murakami
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 代謝産物による中枢性炎症制御メカニズムの解明2021

    • Author(s)
      田中 勇希, 長谷部 理絵, 北條 慎太郎, 樋口 まどか, 上村 大輔, 村上 正晃
    • Organizer
      量子生命科学先端フォーラム 2021冬の研究会
    • Related Report
      2021 Research-status Report
  • [Remarks] 北海道大学遺伝子病制御研究所・量子生命科学研究所・生理学研究所 村上研HP

    • URL

      https://www.igm.hokudai.ac.jp/neuroimmune/

    • Related Report
      2023 Annual Research Report
  • [Remarks] 北海道大学 遺伝子病制御研究所 分子神経免疫学分野

    • URL

      https://www.igm.hokudai.ac.jp/neuroimmune/

    • Related Report
      2021 Research-status Report

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

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