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Dysfunction of the gingival epithelial barrier on the induction of neutrophil extracellular traps by periodontopathogenic bacteria

Research Project

Project/Area Number 19K10143
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 57030:Conservative dentistry-related
Research InstitutionTohoku University

Principal Investigator

Tada Hiroyuki  東北大学, 歯学研究科, 講師 (70431632)

Co-Investigator(Kenkyū-buntansha) 西岡 貴志  東北大学, 歯学研究科, 講師 (50641875)
松下 健二  国立研究開発法人国立長寿医療研究センター, 研究所 口腔疾患研究部, 部長 (90253898)
Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords慢性歯周炎 / 歯周病原細菌 / Porphyromonas gingivalis / Fusobacterium nucleatum / 細胞外トラップ / 歯肉上皮バリア破綻 / 好中球 / マスト細胞 / 好中球細胞外トラップ / 口腔粘膜バリア破綻 / バリア破綻
Outline of Research at the Start

慢性歯周炎において、歯周病原細菌により誘導される慢性炎症は歯周組織を破壊する主体となることから、歯周病における慢性炎症の病態解明は大きな意義を持つ。本研究は、歯周病原細菌の感染により好中球が産生する好中球細胞外トラップ(NETs)が、口腔粘膜のバリア機能を低下させ慢性炎症を誘導することを検討する。慢性歯周炎に慢性炎症が誘導される要因として、歯周ポケットにおける歯周病原細菌の慢性感染と好中球の多量な集積が挙げられる。よって、慢性歯周炎の歯周ポケットでは恒常的に好中球がNETsを産生していることが推察されることから、本研究では歯周病の慢性炎症の制御を目指した予防・治療法の基盤となる検討を行う。

Outline of Final Research Achievements

In chronic periodontitis, periodontal tissue is destroyed by chronic inflammation caused by periodontopathogenic bacteria. This study investigated the mechanisms by which neutrophil extracellular traps (NETs) released by neutrophils in response to infection with periodontopathogenic bacteria disrupt the oral mucosal barrier and exacerbate periodontal disease. Fusobacterium nucleatum induced the release of NETs from neutrophils, which markedly expressed macrophage migration inhibitory factor. F. nucleatum also released the release of extracellular traps from mast cells, which in turn induced an inflammatory response in macrophages. On the other hand, gingipains, proteases produced by Porphyromonas gingivalis, degrades plasminogen activator inhibitor-1 (PAI-1) produced by endothelial cells and delayed wound healing in the vascular endothelium. These findings suggest that chronic inflammation caused by periodontopathogenic bacteria induces dysfunction of the oral mucosal barrier.

Academic Significance and Societal Importance of the Research Achievements

歯周病は、口のなかに常在する歯周病菌による感染症で、持続的な感染により引き起こされる慢性炎症が歯を支える顎の骨を破壊する。よって、慢性炎症のメカニズム解明は、歯周病の予防に重要な意味を持つ。本研究は、歯周病菌が慢性炎症を引き起こし、歯ぐきを支える粘膜バリアを破壊することを明らかにした。歯周病菌の感染に対して、免疫細胞の好中球やマスト細胞は細胞外トラップと呼ばれるクモの巣状の網を噴射し細菌を破壊するが、細胞外トラップは炎症も引き起こすことを明らかにした。また、歯周病菌の持つ酵素であるジンジパインは、血管の修復を遅延させることを明らかにした。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (34 results)

All 2023 2022 2021 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (9 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 9 results,  Open Access: 5 results) Presentation (21 results) (of which Int'l Joint Research: 2 results,  Invited: 2 results) Book (2 results) Remarks (1 results)

  • [Int'l Joint Research] University of Louisville(米国)

    • Related Report
      2021 Research-status Report
  • [Journal Article] Hericium erinaceus ethanol extract and ergosterol exert anti-inflammatory activities by neutralizing lipopolysaccharide-induced pro-inflammatory cytokine production in human monocytes2022

    • Author(s)
      Tada Hiroyuki、Kawahara Kazuyoshi、Osawa Hiraku、Song Li-Ting、Numazaki Kento、Kawai Junya、Onoue Sakura、Nishioka Takashi、Nemoto Eiji、Matsushita Kenji、Sugawara Shunji
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 636 Pages: 1-9

    • DOI

      10.1016/j.bbrc.2022.10.090

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Reactivation of p53 by RITA Induces Apoptosis in Human Oral Squamous Cell Carcinoma Cells2022

    • Author(s)
      ENDO MANABU、NISHIOKA TAKASHI、NUMAZAKI KENTO、HASEGAWA HIROSHI、TAKAHASHI TETSU、SUGAWARA SHUNJI、TADA HIROYUKI
    • Journal Title

      Anticancer Research

      Volume: 42 Issue: 6 Pages: 2931-2937

    • DOI

      10.21873/anticanres.15775

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of Ternary Ti-Ag-Cu Alloys with Excellent Mechanical Properties and Antibiofilm Activity2022

    • Author(s)
      Togawa Genichi、Takahashi Masatoshi、Tada Hiroyuki、Takada Yukyo
    • Journal Title

      Materials

      Volume: 15 Issue: 24 Pages: 9011-9011

    • DOI

      10.3390/ma15249011

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extracellular Vesicles Derived From Murine Cementoblasts Possess the Potential to Increase Receptor Activator of Nuclear Factor-κB Ligand-Induced Osteoclastogenesis2022

    • Author(s)
      Sato Rei、Maruyama Kentaro、Nemoto Eiji、Sakisaka Yukihiko、Suzuki Shigeki、Li Jiajun、Numazaki Kento、Tada Hiroyuki、Yamada Satoru
    • Journal Title

      Frontiers in Physiology

      Volume: 13 Pages: 825596-825596

    • DOI

      10.3389/fphys.2022.825596

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Porphyromonas gingivalis Gingipains-Mediated Degradation of Plasminogen Activator Inhibitor-1 Leads to Delayed Wound Healing Responses in Human Endothelial Cells.2021

    • Author(s)
      Song LT, Tada H, Nishioka T, Nemoto E, Imamura T, Potempa J, Li CY, Matsushita K, Sugawara S
    • Journal Title

      J Innate Immun

      Volume: Nov 25 Issue: 4 Pages: 1-14

    • DOI

      10.1159/000519737

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Nitrogen-containing bisphosphonates and lipopolysaccharide mutually augment inflammation via adenosine triphosphate (ATP)-mediated and interleukin 1β (IL-1β)-mediated production of neutrophil extracellular traps (NETs)2021

    • Author(s)
      Kanan Bando, Toshinobu Kuroishi, Hiroyuki Tada, Takefumi Oizumi, Yukinori Tanaka, Tetsu Takahashi, Itaru Mizoguchi, Shunji Sugawara, Yasuo Endo
    • Journal Title

      Journal of Bone and Mineral Research

      Volume: 36 Issue: 9 Pages: 1866-1878

    • DOI

      10.1002/jbmr.4384

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nicotine exposure induces the proliferation of oral cancer cells through the α7 subunit of the nicotinic acetylcholine receptor.2019

    • Author(s)
      Nishioka T, Tada H, Ibaragi S, Chen CY, Sasano T.
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 509(2) Issue: 2 Pages: 514-520

    • DOI

      10.1016/j.bbrc.2018.12.154

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Dectin-2-Mediated Signaling Leads to Delayed Skin Wound Healing through Enhanced Neutrophilic Inflammatory Response and Neutrophil Extracellular Trap Formation.2019

    • Author(s)
      Miura T, Kawakami K, Kanno E, Tanno H, Tada H, Sato N, Masaki A, Yokoyama R, Kawamura K, Kitai Y, Takagi N, Yamaguchi K, Yamaguchi N, Kyo Y, Ishii K, Imai Y, Saijo S, Iwakura Y, Tachi M.
    • Journal Title

      J Invest Dermatol

      Volume: 139(3) Issue: 3 Pages: 702-711

    • DOI

      10.1016/j.jid.2018.10.015

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Porphyromonas gingivalis induces the production of interleukin-31 by human mast cells, resulting in dysfunction of the gingival epithelial barrier.2018

    • Author(s)
      Tada Hiroyuki, Nishioka Takashi, Takase Aya, Numazaki Kento, Bando Kanan, Matsushita Kenji.
    • Journal Title

      Cell Microbiology

      Volume: 21 Issue: 3 Pages: e12972-e12972

    • DOI

      10.1111/cmi.12972

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] The functional role of neutrophils in RANKL-induced osteoclastogenesis.2023

    • Author(s)
      Numazaki, K., Tada, H., Nishioka, T., Matsushita, K., Mizoguchi, I., Sugawara, S.
    • Organizer
      2023 Annual Meeting of ADEAP CA+inD International Symposium
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 日本学術会議シンポジウム「口腔と全身のネットワーク 脈管系から生命現象を理解する」歯周病原細菌による生体バリア破綻と血管修復障害2022

    • Author(s)
      多田 浩之
    • Organizer
      第64回歯科基礎医学会学術大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Neutrophil extracellular trapsのdouble-stranded DNAは破骨細胞分化を制御する2022

    • Author(s)
      沼崎 研人,西岡 貴志,松下 健二,多田 浩之
    • Organizer
      第27回日本エンドトキシン・自然免疫研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Porphyromonas gingivalisジンジパインはヒト血管内皮細胞のPAI-1を分解し,血管内皮の創傷治癒を遅延させる2022

    • Author(s)
      多田 浩之,西岡 貴志,松下 健二,菅原 俊二
    • Organizer
      第64回歯科基礎医学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Neutrophil extracellular trapsによるRANKL誘導性破骨細胞の分化制御2022

    • Author(s)
      沼崎 研人,多田 浩之,松下 健二,溝口 到,菅原 俊二
    • Organizer
      第64回歯科基礎医学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Porphyromonas gingivalis線毛はLPSによるヒト単球のインターロイキン-6産生を相乗的に誘導する2022

    • Author(s)
      遠山 学,多田 浩之,沼崎 研人,松下 健二,菅原 俊二
    • Organizer
      第64回歯科基礎医学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Ti-Au合金とTi-Cu合金のバイオフィルム形成抑制能2022

    • Author(s)
      高橋 正敏,多田 浩之,高田 雄京
    • Organizer
      第64回歯科基礎医学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Ti-Pt合金とTi-Nb合金のバイオフィルム形成抑制能2022

    • Author(s)
      高田 雄京,多田 浩之,高橋 正敏
    • Organizer
      第64回歯科基礎医学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] セメント芽細胞由来エクソソームによる破骨細胞分化制御 RANKL誘導性破骨細胞形成に対する増強作用2022

    • Author(s)
      佐藤 令,丸山 顕太郎,根本 英二,向坂 幸彦,鈴木 茂樹,沼崎 研人,多田 浩之,山田 聡
    • Organizer
      第65回秋季日本歯周病学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Exacerbation of inflammation in periodontitis: Porphyromonas gingivalis fimbriae induce synergistic interleukin-6 production in human monocytes2022

    • Author(s)
      遠山 学,多田 浩之,菅原 俊二
    • Organizer
      令和4年度スチューデント・クリニシャン・リサーチ・プログラム
    • Related Report
      2022 Annual Research Report
  • [Presentation] Porphyromonas gingivalisジンジパインによるヒト血管内皮細胞のPAI-1分解作用2021

    • Author(s)
      Song Li-Ting、松下健二、多田浩之
    • Organizer
      第94回日本細菌学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] P. gingivalisならびにF. nucleatum LPSはE. coli LPSによるヒト単球のIL-6産生を増強する2021

    • Author(s)
      坂本雄哉、尾之上さくら、川原一芳、松下健二、多田浩之
    • Organizer
      第94回日本細菌学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] ヤマブシタケエタノール抽出物によるエンドトキシン中和作用2021

    • Author(s)
      大沢啓、尾之上さくら、川原一芳、松下健二、多田浩之
    • Organizer
      第94回日本細菌学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] Proteolysis of PAI-1 by P. gingivalis gingipains leading to delayed wound healing responses in endothelial cells2021

    • Author(s)
      Tada H, Song LT, Imamura T, Potempa J, Matsushita K, Sugawara S.
    • Organizer
      16th Meeting of the International Endotoxin and Innate Immunity Society
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Porphyromonas gingivalisジンジパインによる血管内皮細胞のPAI-1分解と創傷治癒遅延2021

    • Author(s)
      多田浩之、松下健二、根本英二
    • Organizer
      第64回秋季日本歯周病学会学術大会
    • Related Report
      2021 Research-status Report
  • [Presentation] Proteolysis of PAI-1 in human endothelial cells by gingipains from Porphyromonas gingivalis2021

    • Author(s)
      Liting Song、松下健二、多田浩之
    • Organizer
      第94回日本細菌学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] P. gingivalis and F. nucleatum LPS augment E. coli LPS-induced IL-6 production by human monocytes2021

    • Author(s)
      坂本雄哉、尾之上さくら、川原一芳、松下健二、多田浩之
    • Organizer
      第94回日本細菌学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Hericium erinaceus ethanol extracts have endotoxin-neutralizing activity2021

    • Author(s)
      大沢啓、尾之上さくら、川原一芳、松下健二、多田浩之
    • Organizer
      第94回日本細菌学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Fusobacterium nucleatum感染によりマスト細胞が産生する細胞外トラップは、MIF依存的に炎症を誘導する2019

    • Author(s)
      多田浩之、西岡貴志、松下健二、菅原俊二
    • Organizer
      第61回歯科基礎医学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Cysteine proteinases from Porphyromonas gingivalis induces the production of IL-31 by mast cells, resulting in downregulation of claudin-1 in gingival epithelial cells.2019

    • Author(s)
      Hiroyuki Tada, Kenji Matsushita, Shunji Sugawara
    • Organizer
      第48回日本免疫学会学術大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 歯周病原細菌に対する自然免疫応答がもたらす慢性炎症と生体バリア破綻2019

    • Author(s)
      多田浩之
    • Organizer
      第25回日本エンドトキシン・自然免疫研究会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Book] エンドトキシン・自然免疫研究23巻2020

    • Author(s)
      多田浩之
    • Total Pages
      86
    • Publisher
      医学図書出版株式会社
    • Related Report
      2020 Research-status Report
  • [Book] エンドトキシン・自然免疫研究22 エンドトキシン・自然免疫研究の新たな可能性を求めて2019

    • Author(s)
      多田浩之、西岡貴志、松下健二、尾之上さくら、川原一芳
    • Total Pages
      82
    • Publisher
      医学図書出版株式会社
    • Related Report
      2019 Research-status Report
  • [Remarks] 歯周病菌が血管の修復を妨げる仕組みを発見 -歯周病菌は血管内皮細胞の創傷治癒を遅延させる-

    • URL

      https://www.tohoku.ac.jp/japanese/2021/12/press20211209-02-tooth.html

    • Related Report
      2021 Research-status Report

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Published: 2019-04-18   Modified: 2024-01-30  

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