Elucidation of molecular pathogenesis in bacterial RNA-induced cytokine storm

• Project/Area Number: 17K10012
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Hirosaki University
• Principal Investigator: Matsumiya Tomoh 弘前大学, 医学研究科, 助教 (30344592)
• Co-Investigator(Kenkyū-buntansha): 姫野 俵太 弘前大学, 農学生命科学部, 教授 (80208785)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 感染症 / 自然免疫応答 / 細菌学 / 感染免疫学 / 細菌感染症 / 自然免疫 / サイトカイン / 内科 / 免疫学

Outline of Final Research Achievements

Despite advances in medical technology, case fatality rate of severe sepsis does not improve we sought to explore novel targets for the cause of cytokine storms, which are the main cause of severe sepsis caused by bacterial infection, and focused on bacterial-specific RNA. In this study, we verified the cytokine-inducing ability of bacterial-specific RNA.
We found that the purified bacterial-specific RNA induces cytokine production in dendritic cells, and the induction depends on the pattern recognition receptor. The results were also observed in a mouse model, revealing that such RNA is an strong inflammatory factor including cytokine induction.

Academic Significance and Societal Importance of the Research Achievements

本課題の結果から、これまで知られていたエンドトキシン以外にも、細菌由来の成分である細菌特異的RNAが強力なサイトカイン誘導能を有することが明らかになった。この成果はサイトカインストームに対する新たな治療戦略の基盤となる可能性がある。
敗血症治療において重症化の予兆を早期に発見することは生命予後に直結することが知られている。本課題の成果の応用は、サイトカインストーム発症の予兆発見に向けた診断技術開発につながる可能性を示した。

Research Products

• [Journal Article] Daily Brazilian green propolis intake elevates blood artepillin C levels in humans (2021)
  • Author(s): Ding Jiangli、Matsumiya Tomoh、Hayakari Ryo、Shiba Yuko、Kawaguchi Shogo、Seya Kazuhiko、Ueno Kayo、Imaizumi Tadaatsu
  • Journal Title: Journal of the Science of Food and Agriculture Volume: － Issue: 11 Pages: 4855-4861
  • DOI: 10.1002/jsfa.11132
  • Peer Reviewed
• [Journal Article] Tryptanthrin suppresses double-stranded RNA-induced CXCL10 expression via inhibiting the phosphorylation of STAT1 in human umbilical vein endothelial cells (2021)
  • Author(s): Kawaguchi Shogo、Sakuraba Hirotake、Kikuchi Hidezumi、Numao Noriyuki、Asari Taka、Hiraga Hiroto、Ding Jiangli、Matsumiya Tomoh、Seya Kazuhiko、Fukuda Shinsaku、Imaizumi Tadaatsu
  • Journal Title: Molecular Immunology Volume: 129 Pages: 32-38
  • DOI: 10.1016/j.molimm.2020.11.003
  • Peer Reviewed / Open Access
• [Journal Article] Toll-Like Receptor 3 as a Recurrence Risk Factor and a Potential Molecular Therapeutic Target in Colorectal Cancer (2020)
  • Author(s): Yoshida Tatsuya、Miura Takuya、Matsumiya Tomoh、Yoshida Hidemi、Morohashi Hajime、Sakamoto Yoshiyuki、Kurose Akira、Imaizumi Tadaatsu、Hakamada Kenichi
  • Journal Title: Clinical and Experimental Gastroenterology Volume: Volume 13 Pages: 427-438
  • DOI: 10.2147/ceg.s252157
  • Peer Reviewed
• [Journal Article] Endothelial expression of fractalkine (CX3CL1) is induced by Toll-like receptor 3 signaling in cultured human glomerular endothelial cells (2019)
  • Author(s): Hirono Koji、Imaizumi Tadaatsu、Aizawa Tomomi、Watanabe Shojiro、Tsugawa Koji、Shiratori Toshihiro、Kawaguchi Shogo、Seya Kazuhiko、Matsumiya Tomoh、Ito Etsuro、Tanaka Hiroshi
  • Journal Title: Modern Rheumatology Volume: - Issue: 6 Pages: 1-8
  • DOI: 10.1080/14397595.2019.1682768
  • Peer Reviewed
• [Journal Article] Interferon-induced transmembrane protein 1 and Myxovirus resistance protein 1 are induced by polyinosinic-polycytidylic acid in cultured hCMEC/D3 human cerebral microvascular endothelial cells (2019)
  • Author(s): Imaizumi Tadaatsu、Satake Urara、Miyashita Ruri、Kawaguchi Shogo、Matsumiya Tomoh、Seya Kazuhiko、Ding Jiangli、Tanaka Hiroshi
  • Journal Title: Journal of Neuroimmunology Volume: 337 Pages: 577047-577047
  • DOI: 10.1016/j.jneuroim.2019.577047
  • Peer Reviewed
• [Journal Article] Melanoma Differentiation-Associated Gene 5 Positively Modulates TNF-α-Induced CXCL10 Expression in Cultured HuH-7 and HLE Cells. (2019)
  • Author(s): Shogo Kawaguchi、 Hirotake Sakuraba、 Toshihiro Haga、 Tomoh Matsumiya、 Kazuhiko Seya、 Tetsu Endo、 Naoya Sawada、 Chikara Iino、 Hidezumi Kikuchi、 Hiroto Hiraga、 Shinsaku Fukuda、 Tadaatsu Imaizumi
  • Journal Title: Inflammation Volume: 42 Issue: 6 Pages: 2095-2104
  • DOI: 10.1007/s10753-019-01073-3
  • Peer Reviewed / Open Access
• [Journal Article] Role of the ISR-ATF4 pathway and its cross talk with Nrf2 in mitochondrial quality control (2019)
  • Author(s): Kasai S, Yamazaki H, Tanji K, Engler MJ, Matsumiya T, Itoh K.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 64 Issue: 1 Pages: 1-12
  • DOI: 10.3164/jcbn.18-37
  • NAID: 130007542293
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Journal Article] Cytosolic sensors of viral RNA are involved in the production of interleukin-6 via Toll-like receptor 3 signaling in human glomerular endothelial cells (2019)
  • Author(s): Liu Q, Imaizumi T, Aizawa T, Hirono K, Kawaguchi S, Watanabe S, Tsugawa K, Matsumiya T, Seya K, Yoshida H, Tanaka H
  • Journal Title: Kidney Blood Pressure Res Volume: 44 Issue: 1 Pages: 62-71
  • DOI: 10.1159/000498837
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Toll-like receptor 3 signaling contributes to regional neutrophil recruitment in cultured human glomerular endothelial cells. (2018)
  • Author(s): Liu Q, Imaizumi T, Kawaguchi S, Aizawa T, Matsumiya T, Watanabe S, Tsugawa K, Yoshida H, Tsuruga K, Joh K, Kijima H, Tanaka H
  • Journal Title: Nephron Volume: 139 Issue: 4 Pages: 349-358
  • DOI: 10.1159/000489507
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Essential Role of Double-Stranded RNA Dependent Antiviral Signaling in the Degradation of Nonself Single-Stranded RNA in Nonimmune Cells (2018)
  • Author(s): Kimura Sayaka、Matsumiya Tomoh、Shiba Yuko、Nakanishi Michi、Hayakari Ryo、Kawaguchi Shogo、Yoshida Hidemi、Imaizumi Tadaatsu
  • Journal Title: The Journal of Immunology Volume: 201 Issue: 3 Pages: 1044-1052
  • DOI: 10.4049/jimmunol.1800456
  • Peer Reviewed
• [Journal Article] Interferon-stimulated gene 60 (ISG60) constitutes a negative feedback loop in the downstream of TLR3 signaling in hCMEC/D3 cells (2018)
  • Author(s): Imaizumi Tadaatsu、Sassa Naoko、Kawaguchi Shogo、Matsumiya Tomoh、Yoshida Hidemi、Seya Kazuhiko、Shiratori Toshihiro、Hirono Koji、Tanaka Hiroshi
  • Journal Title: Journal of Neuroimmunology Volume: 324 Pages: 16-21
  • DOI: 10.1016/j.jneuroim.2018.08.016
  • Peer Reviewed
• [Journal Article] Chloroquine attenuates TLR3/IFN-β signaling in cultured normal human mesangial cells: A possible protective effect against renal damage in lupus nephritis. (2017)
  • Author(s): Imaizumi T, Hayakari R, Matsumiya T, Yoshida H, Tsuruga K, Watanabe S, Kawaguchi S, Tanaka H.
  • Journal Title: Mod Rheumatol Volume: - Issue: 6 Pages: 1004-8
  • DOI: 10.1080/14397595.2017.1289646
  • Peer Reviewed / Open Access
• [Journal Article] Cylindromatosis (CYLD), a deubiquitinase, attenuates inflammatory signaling pathways by activating Toll-like receptor 3 in human mesangial cells. (2017)
  • Author(s): Imaizumi T, Hayakari R, Watanabe S, Aizawa T, Matsumiya T, Yoshida H, Tsuruga K, Kawaguch S, Tanaka H
  • Journal Title: Kidney and Blood Pressure Research Volume: 42 Issue: 5 Pages: 942-950
  • DOI: 10.1159/000485084
  • NAID: 120006557467
  • Peer Reviewed / Open Access