The peritoneum omentum exosomes in the septic immune paralysis

• Project/Area Number: 16K15759
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Emergency medicine
• Research Institution: Mie 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: ¥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。

Research Products

• [Journal Article] Talin-2 regulates integrin functions in exosomes (2019)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-adhesive effects of human soluble thrombomodulin and its domains (2019)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exosomal regulation of lymphocyte homing to the gut (2018)
  • 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
  • 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 expression (2018)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gap junction-mediated regulation of endothelial cellular stiffness (2017)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
• [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
• [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
• [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
  • 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
• [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
• [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
• [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
• [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
  • 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