Elucidation of the mechanism by which exosomal PD-L1 induces septic immune paralysis

• Project/Area Number: 21K09015
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55060:Emergency medicine-related
• 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): 島岡 要 三重大学, 医学系研究科, 教授 (40281133) ; 朴 恩正 三重大学, 医学系研究科, 准教授 (20644587) ; 赤間 悠一 三重大学, 医学部附属病院, 助教 (40763313) ; 高娃 阿栄 三重大学, 医学系研究科, 助教 (50643805)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Granted (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2022: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 細胞外小胞 / 敗血症 / SIRS / インテグリン / PD-L1 / Tリンパ球 / β1、β2、β3インテグリン / ショック / 免疫麻痺 / 腎機能障害 / エキソソームPDL1 / エフェクターT細胞の疲弊化 / 制御性T細胞（Treg）

Outline of Research at the Start

本研究では「仮説1：敗血症患者の血液中に存在するエキソソームPD-L1がエフェクターT細胞の疲弊化（T細胞の機能低下、リンパ球の減少）を誘導し、仮説2：さらにエキソソーム内に含有されるmiRNAが制御性T細胞（Treg）の機能強化を引き起こして敗血症の免疫麻痺に中心的役割を果たしている」という2つの互いに関連する学術的な問いを検証する。

Outline of Annual Research Achievements

血漿中の細胞外小胞（EV）は、がんや炎症性疾患の発症に重要な細胞間コミュニケーションを仲介している。EVは、標的特異性を制御するインテグリンや、リンパ球の活性化を抑制するプログラム細胞死リガンド1、2（PD-L1、2）などを発現している。しかし、全身性炎症反応症候群（SIRS）や敗血症におけるEV上のこれらの分子の役割については、ほとんど解明されていない。今年度は、SIRSおよび敗血症におけるインテグリンおよびPD-1リガンドのEV発現が、健常対照者と比較してどのように異なる可能性があるかを調べ、その発現と病態を反映する臨床パラメータとの相関を検討した。敗血症を伴わないSIRS患者27人、敗血症患者27
人、健常ボランティア18人を対象とした。血漿試料からEVを分離した。3つの主要なインテグリン（β1、β2、β3インテグリン）、PD-L1および2の発現を測定した。β2インテグリンとPD-L2のEV発現は、健常対照者と比較して敗血症患者で有意に増加した。PD-L1のEV発現は、敗血症およびSIRSでは上昇しなかったが、循環血中可溶性PD-L1濃度（エキソソーム含有）は敗血症で有意に高値であった。さらに、敗血症患者におけるβ2インテグリンのEV発現は、低血圧および腎機能低下と相関していた。さらに、可溶性PD-L1レベルは、敗血症の重症度、腎機能障害、中枢神経系機能障害と相関していた。これらの結果は、多臓器不全につながる全身的な免疫活性化を伴う敗血症の病態に、EVのβ2インテグリンだけでなく、EVのPD-L2や可溶性PD-L1が関与している可能性を示唆していると考えられる。

Current Status of Research Progress

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

Reason

重症患者の血液採取が予想より早くできたため。

Strategy for Future Research Activity

患者血液データの解析を早めて論文作成を行う。

Research Products

• [Journal Article] MicroRNA Profiles in Intestinal Epithelial Cells in a Mouse Model of Sepsis (2023)
  • Author(s): Caidengbate Siqingaowa、Akama Yuichi、Banerjee Anik、Mokmued Khwanchanok、Kawamoto Eiji、Gaowa Arong、McCullough Louise D.、Shimaoka Motomu、Lee Juneyoung、Park Eun Jeong
  • Journal Title: Cells Volume: 12 Issue: 5 Pages: 726-726
  • DOI: 10.3390/cells12050726
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Continuous High Positive-End Expiratory Pressure May Worsen Renal Function in Patients With Acute Respiratory Distress Syndrome: Retrospective Analyses of a Nationwide, Multicenter Observational Study in Japan (2023)
  • Author(s): Yokoyama Kazuto、Kaneko Tadashi、Ieki Yohei、Ito Asami、Kawamoto Eiji、Suzuki Kei、Ishikura Ken、Imai Hiroshi
  • Journal Title: Cureus Volume: 15 Pages: 35233-35233
  • DOI: 10.7759/cureus.35233
  • Peer Reviewed / Open Access
• [Journal Article] Tetraploidy-linked sensitization to CENP-E inhibition in human cells. (2023)
  • Author(s): Yoshizawa Koya、Matsura Akira、Shimada Masaya、Ishida‐Ishihara Sumire、Sato Fuyu、Yamamoto Takahiro、Yaguchi Kan、Kawamoto Eiji、Kuroda Taruho、Matsuo Kazuya、Tamaoki Nobuyuki、Sakai Ryuichi、Shimada Yasuhito、Mishra Mithilesh、Uehara Ryota
  • Journal Title: Molecular Oncology Volume: 10 Issue: 6 Pages: 13379-13379
  • DOI: 10.1002/1878-0261.13379
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Conservative medical management combined with follow-up multidetector computed tomography of tracheobronchial injury caused by penetrating injuries: A case report (2022)
  • Author(s): Takahashi Tsuyoshi、Kaneko Tadashi、Hane Atsuya、Ito Asami、Kawamoto Eiji、Suzumura Misato、Ueda Koki、Shinoda Mari、Ito Atsushi、Imai Hiroshi
  • Journal Title: Trauma Case Reports Volume: 42 Pages: 100710-100710
  • DOI: 10.1016/j.tcr.2022.100710
  • Peer Reviewed / Open Access
• [Journal Article] Sequential organ failure assessment score as a predictor of the outcomes of patients hospitalized for classical or exertional heatstroke (2022)
  • Author(s): Yokoyama Kazuto、Kaneko Tadashi、Ito Asami、Ieki Yohei、Kawamoto Eiji、Suzuki Kei、Ishikura Ken、Imai Hiroshi、Kanda Jun、Yokobori Shoji
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 16373-16373
  • DOI: 10.1038/s41598-022-20878-1
  • Peer Reviewed / Open Access
• [Journal Article] Possible Metastatic Stage-Dependent ILC2 Activation Induces Differential Functions of MDSCs through IL-13/IL-13Rα1 Signaling during the Progression of Breast Cancer Lung Metastasis (2022)
  • Author(s): Ito Atsushi、Akama Yuichi、Satoh-Takayama Naoko、Saito Kanako、Kato Takuma、Kawamoto Eiji、Gaowa Arong、Park Eun Jeong、Takao Motoshi、Shimaoka Motomu
  • Journal Title: Cancers Volume: 14 Issue: 13 Pages: 3267-3267
  • DOI: 10.3390/cancers14133267
  • Peer Reviewed / Open Access
• [Journal Article] miRNA-200c-3p targets talin-1 to regulate integrin-mediated cell adhesion. (2021)
  • Author(s): Obeng G, Park EJ, Appiah MG, Kawamoto E, Gaowa A, Shimaoka M.
  • Journal Title: Sci Rep. Volume: 11 Issue: 1 Pages: 21597-21597
  • DOI: 10.1038/s41598-021-01143-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cytoskeletal Actin Structure in Osteosarcoma Cells Determines Metastatic Phenotype via Regulating Cell Stiffness, Migration, and Transmigration (2021)
  • Author(s): Kita Kouji、Asanuma Kunihiro、Okamoto Takayuki、Kawamoto Eiji、Nakamura Koichi、Hagi Tomohito、Nakamura Tomoki、Shimaoka Motomu、Sudo Akihiro
  • Journal Title: Current Issues in Molecular Biology Volume: 43 Issue: 3 Pages: 1255-1266
  • DOI: 10.3390/cimb43030089
  • Peer Reviewed / Open Access
• [Journal Article] Elevated Plasma Soluble PD-L1 Levels in Out-of-Hospital Cardiac Arrest Patients (2021)
  • Author(s): Sumiyoshi Miho、Kawamoto Eiji、Nakamori Yuki、Esumi Ryo、Ikejiri Kaoru、Shinkai Toru、Akama Yuichi、Ito-Masui Asami、Imai Hiroshi、Gaowa Arong、Park Eun Jeong、Shimaoka Motomu
  • Journal Title: Journal of Clinical Medicine Volume: 10 Issue: 18 Pages: 4188-4188
  • DOI: 10.3390/jcm10184188
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Substrate stiffness modulates endothelial cell function via the YAP-Dll4-Notch1 pathway (2021)
  • Author(s): Matsuo Eri、Okamoto Takayuki、Ito Atsushi、Kawamoto Eiji、Asanuma Kunihiro、Wada Koichiro、Shimaoka Motomu、Takao Motoshi、Shimamoto Akira
  • Journal Title: Experimental Cell Research Volume: 408 Issue: 1 Pages: 112835-112835
  • DOI: 10.1016/j.yexcr.2021.112835
  • Peer Reviewed / Open Access
• [Journal Article] Prevalence and predictors of direct discharge home following hospitalization of patients with serious adverse events managed by the rapid response system in Japan: a multicenter, retrospective, observational study (2021)
  • Author(s): Takashi Hongo, Hiromichi Naito, Toshifumi Fujiwara, Takaki Naito, Yosuke Homma, Yoshihisa Fujimoto, Morooka Takaya, Yuji Yamamori, Taka-Aki Nakada, Tsuyoshi Nojima, Atsunori Nakao, Shigeki Fujitani
  • Journal Title: Acute Medicine & Surgery Volume: 8 Issue: 1 Pages: 1-8
  • DOI: 10.1002/ams2.690
  • Peer Reviewed / Open Access
• [Journal Article] Recombinant soluble thrombomodulin accelerates epithelial stem cell proliferation in mouse intestinal organoids and promotes the mucosal healing in colitis (2021)
  • Author(s): Gaowa A, Park EJ, Kawamoto E, Qin Y, Shimaoka M.
  • Journal Title: J Gastroenterol Hepatol. Volume: 36 Issue: 11 Pages: 3149-3157
  • DOI: 10.1111/jgh.15656
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cellular and exosomal regulations of sepsis-induced metabolic alterations (2021)
  • Author(s): Appiah G. Michael, Park Eun Jeong, Akama Y, Nakamori Y, Kawamoto E, Gaowa A, Shimaoka M
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 15 Pages: 8295-8295
  • DOI: 10.3390/ijms22158295
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sociometric wearable devices for studying human behavior in corporate and healthcare workplaces (2021)
  • Author(s): Ito-Masui Asami、Kawamoto Eiji、Esumi Ryo、Imai Hiroshi、Shimaoka Motomu
  • Journal Title: BioTechniques Volume: 71 Issue: 1 Pages: 392-399
  • DOI: 10.2144/btn-2020-0160
  • Peer Reviewed / Open Access
• [Journal Article] Endothelial connexin-integrin crosstalk in vascular inflammation (2021)
  • Author(s): Okamoto Takayuki、Park Eun Jeong、Kawamoto Eiji、Usuda Haruki、Wada Koichiro、Taguchi Akihiko、Shimaoka Motomu
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease Volume: 1867 Issue: 9 Pages: 166168-166168
  • DOI: 10.1016/j.bbadis.2021.166168
  • Peer Reviewed / Open Access
• [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 Issue: 4 Pages: 645-645
  • DOI: 10.3390/v13040645
  • Peer Reviewed / Open Access
• [Journal Article] Randomized trial of granulocyte colony-stimulating factor for spinal cord injury (2021)
  • Author(s): Koda Masao、Hanaoka Hideki、Fujii Yasuhisa、Hanawa Michiko、et al.
  • Journal Title: Brain Volume: 144 Issue: 3 Pages: 789-799
  • DOI: 10.1093/brain/awaa466
  • 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: Biochem Biophys Rep. 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: Int J Mol Sci. Volume: 22 Issue: 4 Pages: 1881-1881
  • DOI: 10.3390/ijms22041881
  • Peer Reviewed / Open Access
• [Journal Article] Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest (2021)
  • Author(s): Ikejiri Kaoru、Akama Yuichi、Ieki Yohei、Kawamoto Eiji、Suzuki Kei、Yokoyama Kazuto、Ishikura Ken、Imai Hiroshi
  • Journal Title: Medicine Volume: 100 Issue: 9 Pages: e24980-e24980
  • DOI: 10.1097/md.0000000000024980
  • Peer Reviewed / Open Access
• [Journal Article] Internet-based Individualized Cognitive Behavioral Therapy for Shift Work Sleep Disorder (Empowered by Wellbeing Prediction): A Pilot Study Protocol. (2021)
  • Author(s): Ito-Masui A, Sakamoto R, Yu H,, Sano A, Motomura E, Tanii H, Sakano S, Esumi R, Imai H, Shimaoka M
  • Journal Title: J JMIR Res Protoc. Volume: 10(3) Issue: 3 Pages: e24799-e24799
  • DOI: 10.2196/24799
  • 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] The Lectin-Like Domain of Thrombomodulin Inhibits β1 Integrin-Dependent Binding of Human Breast Cancer-Derived Cell Lines to Fibronectin. (2021)
  • Author(s): Kawamoto E, Nago N, Okamoto T, Gaowa A, Masui-Ito A, Akama Y, Darkwah S, Appiah MG, Myint PK, Obeng G, Ito A, Caidengbate S, Esumi R, Yamaguchi T, Park EJ, Imai H, Shimaoka M.
  • Journal Title: Biomedicines Volume: 9 Issue: 2 Pages: 162-162
  • DOI: 10.3390/biomedicines9020162
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: Biochem Biophys Rep. Volume: 26 Pages: 100932-100932
  • DOI: 10.1016/j.bbrep.2021.100932
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The characteristics, types of intervention, and outcomes of postoperative patients who required rapid response system intervention: A nationwide database analysis (2021)
  • Author(s): Yoshiki Sento, Masayasu Arai, Yuji Yamamori, Shinsuke Fujiwara, Masahiro Tamashiro, Eiji Kawamoto, Takaki Naito, Kazuaki Atagi, Shigeki Fujitani, Satoshi Osaga, Kazuya Sobue, on behalf of the In-Hospital Emergency Study Group
  • Journal Title: Journal of Anesthesia Volume: 35 Issue: 2 Pages: 222-231
  • DOI: 10.1007/s00540-021-02900-4
  • Peer Reviewed / Open Access
• [Journal Article] Sepsis Induces Deregulation of IL-13 Production and PD-1 Expression in Lung Group 2 Innate Lymphoid Cells. (2021)
  • Author(s): Akama Y, Park EJ, Satoh-Takayama N, Gaowa A, Ito A, Kawamoto E, Darkwah S, Appiah MG, Myint PK, Ohno H, Imai H, Shimaoka M.
  • Journal Title: Shock Volume: 55 Issue: 3 Pages: 357-370
  • DOI: 10.1097/shk.0000000000001647
  • Peer Reviewed / Open Access
• [Journal Article] Methods to Study Integrin Functions on Exosomes (2020)
  • Author(s): Kawamoto Eiji、Park Eun Jeong、Shimaoka Motomu
  • Journal Title: Methods in Molecular Biology Volume: 2217 Pages: 265-281
  • DOI: 10.1007/978-1-0716-0962-0_15
  • ISBN: 9781071609613, 9781071609620
  • Peer Reviewed / Open Access