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The peritoneum omentum exosomes in the septic immune paralysis

Research Project

Project/Area Number 16K15759
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Emergency medicine
Research InstitutionMie University

Principal Investigator

SHIMAOKA Motomu  三重大学, 医学系研究科, 教授 (40281133)

Co-Investigator(Kenkyū-buntansha) 朴 恩正  三重大学, 医学系研究科, 准教授 (20644587)
岡本 貴行  島根大学, 学術研究院医学・看護学系, 准教授 (30378286)
江口 暁子  三重大学, 医学系研究科, 特任助教(研究担当) (00598980)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords炎症 / 免疫 / 敗血症 / ショック / 免疫学 / 感染症 / 病理学 / インテグリン / エキソソーム / リンパ球 / 血管内皮 / 粘膜免疫 / ホーミング
Outline of Final Research Achievements

We have studied the research hypothesis that the exosomes secreted from the peritoneum omentum milky spots play a critical role in the suppression of immune system during the course of septic shock. Such exosomes are referred to here as tolerosomes. The tolerosomes act in a paracrine manner to local macrophages, thereby skewing the M1-macrophages to the M2-macrophages. In addition, the tolerosomes travel in the circulation and act in a systemic manner to lymphocytes, thereby upregulating PD-1 and/or inducing regulatory cells. In this way, the torelosomes induce immune paralysis in septic shock. We have tested this hypothesis using mouse CLP model, an established sepsis model. We utilized molecular biological, immunological, and pathohistological approaches to address this important problem.

Academic Significance and Societal Importance of the Research Achievements

1)免疫系の過剰活性ではなく、致死率の高い病態晩期での免疫麻痺に着眼したいこと、2)マクロファージ単体ではなく、大網乳斑という微小環境の変化によるマクロファージ機能の劇的変化を検討したこと、3)「トレロソームによる免疫麻痺」や「炎症による大網乳班リモデリング」という新規病態概念の提唱したことが学術的意義である。
本研究より敗血症病態理解の全く新しい方向性が示されることが予想され、病期や重症度の診断のためのバイオマーカーの開発や、免疫麻痺を解除する新規治療法につながる医学的意義がある。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (19 results)

All 2019 2018 2017 2016

All Journal Article (9 results) (of which Int'l Joint Research: 9 results,  Peer Reviewed: 9 results,  Open Access: 6 results,  Acknowledgement Compliant: 1 results) Presentation (10 results) (of which Invited: 2 results)

  • [Journal Article] Talin-2 regulates integrin functions in exosomes2019

    • Author(s)
      Soe Zay Yar、Prajuabjinda Onmanee、Myint Phyoe Kyawe、Gaowa Arong、Kawamoto Eiji、Park Eun Jeong、Shimaoka Motomu
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 512 Issue: 3 Pages: 429-434

    • DOI

      10.1016/j.bbrc.2019.03.027

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Anti-adhesive effects of human soluble thrombomodulin and its domains2019

    • Author(s)
      Kawamoto Eiji、Nago Nodoka、Okamoto Takayuki、Gaowa Arong、Masui-Ito Asami、Sakakura Yosuke、Akama Yuichi、Soe Zay Yar、Prajuabjinda Onmanee、Darkwah Samuel、Appiah Michael G.、Myint Phyoe Kyawe、Obeng Gideon、Park Eun Jeong、Imai Hiroshi、Shimaoka Motomu
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 511 Issue: 2 Pages: 312-317

    • DOI

      10.1016/j.bbrc.2019.02.041

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Exosomal regulation of lymphocyte homing to the gut2018

    • Author(s)
      Park Eun Jeong、Prajuabjinda Onmanee、Soe Zay Yar、Darkwah Samuel、Appiah Michael G.、Kawamoto Eiji、Momose Fumiyasu、Shiku Hiroshi、Shimaoka Motomu
    • Journal Title

      Blood Advances

      Volume: 3 Issue: 1 Pages: 1-11

    • DOI

      10.1182/bloodadvances.2018024877

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Reduced substrate stiffness promotes M2-like macrophage activation and enhances peroxisome proliferator-activated receptor-gamma expression2018

    • Author(s)
      Okamoto T, Takagi Y, Kawamoto E, Park EJ, Usuda H, Wada K, Shimaoka M
    • Journal Title

      Experimental Cell Research

      Volume: 367 Issue: 2 Pages: 264-273

    • DOI

      10.1016/j.yexcr.2018.04.005

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Gap junction-mediated regulation of endothelial cellular stiffness2017

    • Author(s)
      Okamoto Takayuki、Kawamoto Eiji、Takagi Yoshimi、Akita Nobuyuki、Hayashi Tatsuya、Park Eun Jeong、Suzuki Koji、Shimaoka Motomu
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 6134-6134

    • DOI

      10.1038/s41598-017-06463-x

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Public Response to Scientific Misconduct: Assessing Changes in Public Sentiment Toward the Stimulus-Triggered Acquisition of Pluripotency (STAP) Cell Case via Twitter.2017

    • Author(s)
      2.Gayle A, Shimaoka M
    • Journal Title

      JMIR Public Health Surveill

      Volume: 3 Issue: 2 Pages: e21-e21

    • DOI

      10.2196/publichealth.5980

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] MicroRNA-mediated dynamic control of mucosal immunity in intestinal ecosystem.2017

    • Author(s)
      Park, EJ., Shimaoka, M. and Kiyono, H.
    • Journal Title

      International Immunology

      Volume: - Issue: 4 Pages: 157-163

    • DOI

      10.1093/intimm/dxx019

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] MicroRNA- mediated dynamic control of mucosal immunity.2017

    • Author(s)
      Park EJ, Shimaoka M, Kiyono H.
    • Journal Title

      Int Immunol

      Volume: 印刷中

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] LFA-1 and Mac-1 integrins bind to the serine/threonine-rich domain of thrombomodulin.2016

    • Author(s)
      Okamoto T, Kawamoto E, Takagi Y, Honda G, Suzuki K, Ima H, Shimaoka M
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 473 Issue: 4 Pages: 1005-1012

    • DOI

      10.1016/j.bbrc.2016.04.007

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 炎症時の血管内皮細胞の硬化にリコモジュリンが及ぼす影響の解析2018

    • Author(s)
      岡本貴行,川本英嗣,島岡 要 他
    • Organizer
      第40回日本血栓止血学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 細胞外小胞 (EV) インテグリンの敗血症病態への関与の研究を目的としたCRISPR/Cas9 遺伝子編集技術を用いたインテグリンノックアウトEVの作製.2018

    • Author(s)
      川本英嗣,江口暁子,島岡 要 他
    • Organizer
      第33回日本Shock学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Intraluminally secreted extracellular vesicles from the intestinal epithelial cells in sepsis support mucosal healing.2018

    • Author(s)
      Eun Jeong Park, Michael G Appiah,Samuel Darkwah,Eiji Kawamoto,Motomu Shimaoka.
    • Organizer
      第47回日本免疫学会総会・学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Platelet activation and integrin signaling.2017

    • Author(s)
      島岡 要
    • Organizer
      第39回日本血栓止血学会学術集会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] インテグリン活性化と炎症制御2017

    • Author(s)
      島岡 要
    • Organizer
      第32回日本Shock学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 敗血症患者の細胞外小胞にはインテグリン, PD-L1, PD-L2が発現する2017

    • Author(s)
      川本英嗣,島岡 要 他
    • Organizer
      第32回日本Shock学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] LPS肝炎に続く敗血症性炎症病変における腹部内進展のMRIイメージング2017

    • Author(s)
      長太のどか,島岡 要 他
    • Organizer
      第32回日本Shock学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] β7 Integrin mediated homing of exosomes to the gut.2017

    • Author(s)
      Park EJ, Shimaoka M et al.
    • Organizer
      第46回日本免疫学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] インテグリンの機能制御2016

    • Author(s)
      島岡要
    • Organizer
      第38回日本血栓止血学会学術集会
    • Place of Presentation
      奈良春日野国際フォーラム甍(奈良市)
    • Year and Date
      2016-06-16
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] マクロファージの分化における細胞外基質の硬さの影響2016

    • Author(s)
      岡本貴行,川本英嗣,秋田展幸, 林辰弥,鈴木宏治,島岡要
    • Organizer
      第38回日本血栓止血学会学術集会
    • Place of Presentation
      奈良春日野国際フォーラム甍(奈良市)
    • Year and Date
      2016-06-16
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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