Aberrant skeletal muscle-brain communication in sepsis-associated encephalopathy: Elucidating the pathogenic roles of skeletal muscle-derived exosomes

• Project/Area Number: 19KK0224
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Mie University
• Principal Investigator: 川本 英嗣 三重大学, 医学部附属病院, 講師 (20577415)
• Co-Investigator(Kenkyū-buntansha): 亀井 政孝 三重大学, 医学部附属病院, 教授 (60443503) ; 赤間 悠一 三重大学, 医学部附属病院, 助教 (40763313) ; 中森 裕毅 三重大学, 医学部附属病院, 助教 (80815994) ; 池尻 薫 三重大学, 医学部附属病院, 助教 (90813014)
• Project Period (FY): 2019-10-07 – 2024-03-31
• Project Status: Granted (Fiscal Year 2020)
• Budget Amount: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000); Fiscal Year 2023: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2022: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2021: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: イリシン / 骨格筋エキソソーム / 細胞外小胞 / マイオカイン / マイオソーム / 敗血症 / PICS / ICU-AW / fMRI / miRNA / 敗血症関連脳症 / エキソソーム / ミオカイン

Outline of Research at the Start

感染症に対する免疫系反応の制御不能による多臓器不全である敗血症（Sepsis）は世界で年間数百万人が罹患し、そのうち4人に1人以上が死亡する．敗血症による中枢神経機能障害である敗血症関連脳症（Sepsis-Associated Encephalopathy）は重要な生命予後不良因子であるが、その病態機序は不明である。
本研究では運動器官である骨格筋の“隠れた機能である内分泌能”を介した中枢神経系制御メカニズム「骨格筋-脳コミュニケーション」に着目し、敗血症関連脳症の病態を解明かつ新規治療標的を同定する。

Outline of Annual Research Achievements

細胞外小胞（Extracellular Vesicle: EV）は、細胞間コミュニケーションの重要な担い手として注目されており、組織間のクロストークを媒介している。筋細胞由来のEVとマイオカインは、細胞の分化、増殖、代謝を司る強力なメディエーターであることがわかってきた。筋細胞由来のEV、マイオカイン、マイクロRNA、サイトカイン、ケモカイン、プロスタグランジンなどの生物学的調節因子は、肝臓や脂肪組織などの重要な部位におけるニッチのリモデリングを調節する可能性がある。
今年度は骨格筋由来のマイオカインの1つであるイリシンに注目し、白血球の相互作用について検証した。その結果、イリシン蛋白と白血球インテグリンの接着について同定した。この結果は骨格筋マイオカインが白血球の接着を調整する可能性を示唆している。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

骨格筋由来のエキソソームの抽出に成功した。
さらに骨格筋から放出されるマイオカインの1つであるイリシンと白血球との相互作用について検証した。

Strategy for Future Research Activity

骨格筋マイオカインの１つのイリシンに注目して白血球との相互作用について検討する。さらに血管内皮細胞への影響についても検証を行う。

Research Products

• [Journal Article] The Spike Glycoprotein of SARS-CoV-2 Binds to β1 Integrins Expressed on the Surface of Lung Epithelial Cells. (2021)
  • Author(s): Park EJ, Myint PK, Appiah MG, Darkwah S, Caidengbate S, Ito A, Matsuo E, Gaowa a, Shimaoka M. Kawamoto E,
  • Journal Title: Viruses Volume: 13 Pages: 645-645
  • DOI: 10.3390/v13040645
  • Peer Reviewed / Open Access
• [Journal Article] Irisin supports integrin-mediated cell adhesion of lymphocytes. (2021)
  • Author(s): Myint PK, Ito A, Appiah MG, Obeng G, Darkwah S, Kawamoto E, Gaowa A, Park EJ, Shimaoka M
  • Journal Title: Biochemistry and Biophysics Reports Volume: 26 Pages: 100977-100977
  • DOI: 10.1016/j.bbrep.2021.100977
  • Peer Reviewed / Open Access
• [Journal Article] Remodeling of Bone Marrow Niches and Roles of Exosomes in Leukemia. (2021)
  • Author(s): Yamaguchi T, Kawamoto E, Gaowa A, Park EJ, Shimaoka M.
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Pages: 1881-1881
  • DOI: 10.3390/ijms22041881
  • Peer Reviewed / Open Access
• [Journal Article] Potential Roles of Muscle-Derived Extracellular Vesicles in Remodeling Cellular Microenvironment: Proposed Implications of the Exercise-Induced Myokine, Irisin (2021)
  • Author(s): Darkwah Samuel、Park Eun Jeong、Myint Phyoe Kyawe、Ito Atsushi、Appiah Michael G.、Obeng Gideon、Kawamoto Eiji、Shimaoka Motomu
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 9 Pages: 1-1
  • DOI: 10.3389/fcell.2021.634853
  • Peer Reviewed / Open Access
• [Journal Article] Ligand-competent fractalkine receptor is expressed on exosomes. (2021)
  • Author(s): Park EJ, Myint PK, Appiah MG, Worawattananutai P, Inprasit J, Prajuabjinda O, Soe ZY, Gaowa A, Kawamoto E, Shimaoka M.
  • Journal Title: Biochemistry and Biophysics Reports Volume: 26 Pages: 100932-100932
  • DOI: 10.1016/j.bbrep.2021.100932
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Methods to Study Integrin Functions on Exosomes (2020)
  • Author(s): Kawamoto Eiji、Park Eun Jeong、Shimaoka Motomu
  • Journal Title: Methods Mol Biol. Volume: 2217 Pages: 265-281
  • DOI: 10.1007/978-1-0716-0962-0_15
  • Peer Reviewed / Open Access
• [Journal Article] Integrin-Ligand Interactions in Inflammation, Cancer, and Metabolic Disease: Insights Into the Multifaceted Roles of an Emerging Ligand Irisin (2020)
  • Author(s): Park Eun Jeong、Myint Phyoe Kyawe、Ito Atsushi、Appiah Michael G.、Darkwah Samuel、Kawamoto Eiji、Shimaoka Motomu
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 8 Pages: 1-1
  • DOI: 10.3389/fcell.2020.588066
  • Peer Reviewed / Open Access
• [Journal Article] Targeted remodeling of breast cancer and immune cell homing niches by exosomal integrins. (2020)
  • Author(s): Myint PK, Park EJ, Gaowa A, Kawamoto E, Shimaoka M.
  • Journal Title: Diagnostic Pathology Volume: 15 Pages: 1-1
  • DOI: 10.1186/s13000-020-00959-3
  • Peer Reviewed / Open Access
• [Journal Article] Exosomes in Sepsis and Inflammatory Tissue Injury (2020)
  • Author(s): Park EJ, Appiah MG, Myint PK, Gaowa A, 他2名
  • Journal Title: Current Pharmaceutical Design Volume: 25 Pages: 4486-4495
  • DOI: 10.2174/1381612825666191116125525
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Feasibility of Measuring Face-to-Face Interactions among ICU Healthcare Professionals Using Wearable Sociometric Badges (2020)
  • Author(s): Ito-Masui Asami、Kawamoto Eiji、Nagai Yuki、Takagi Yuto、Ito Mami、Mizutani Noriko、Yano Ken’ichi、Yano Kazuo、Imai Hiroshi、Shimaoka Motomu
  • Journal Title: Am J Respir Crit Care Med. Volume: 201 Pages: 245-247
  • DOI: 10.1164/rccm.201904-0779le
  • Peer Reviewed / Open Access
• [Journal Article] Differential Roles of Dendritic Cells in Expanding CD4 T Cells in Sepsis (2019)
  • Author(s): Darkwah Samuel、Nago Nodoka、Appiah Michael G.、Myint Phyoe Kyawe、Kawamoto Eiji、Shimaoka Motomu、Park Eun Jeong
  • Journal Title: Biomedicines Volume: 7 Pages: 52-52
  • DOI: 10.3390/biomedicines7030052
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: Biochem Biophys Res Commun Volume: 512 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: Biochem Biophys Res Commun Volume: 511 Pages: 312-317
  • DOI: 10.1016/j.bbrc.2019.02.041
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Connexins and Integrins in Exosomes (2019)
  • Author(s): Shimaoka M, Kawamoto E, Gaowa A, Okamoto T, Park EJ
  • Journal Title: Cancers Volume: － Pages: 106-106
  • DOI: 10.3390/cancers11010106
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrin and PD-1 Ligand Expression on Circulating Extracellular Vesicles in Systemic Inflammatory Response Syndrome and Sepsis (2019)
  • Author(s): Kawamoto Eiji、Masui-Ito Asami、Eguchi Akiko、Soe Zay Yar、Prajuabjinda Onmanee、Darkwah Samuel、Park Eun Jeong、Imai Hiroshi、Shimaoka Motomu
  • Journal Title: Shock. Volume: - Pages: 1-1
  • DOI: 10.1097/shk.0000000000001228
  • Peer Reviewed / Open Access / Int'l Joint Research