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Inflammatory cell death during acute-on-chronic kidney injury

Research Project

Project/Area Number 20K17290
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53040:Nephrology-related
Research InstitutionJichi Medical University

Principal Investigator

Komada Takanori  自治医科大学, 医学部, 講師 (90824730)

Project Period (FY) 2020-04-01 – 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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywords慢性腎臓病 / 急性腎障害 / マクロファージ / パイロトーシス / インフラマソーム / 細胞死 / M1マクロファージ / 炎症
Outline of Research at the Start

慢性腎臓病(CKD)の腎組織にはマクロファージを主体とした炎症細胞浸潤が持続し、無菌性炎症が進展に関与する。CKD腎に発症した急性腎障害(AKI)(Acute-on-chronic腎障害)は通常のAKIよりも重症化しやすく、腎予後も極めて悪い。その機序のひとつとして、CKD腎に浸潤した炎症細胞が壊死すると、死細胞残骸が周囲組織に傷害を与える可能性がある。申請者は炎症と細胞死を惹起するインフラマソームに着目し、細胞・動物実験によって炎症細胞死を解析する。本研究により、Acute-on-chronic腎障害重症化の機序解明と制御法開発を目指す。

Outline of Final Research Achievements

Cell death is a physiologically functional process that regulates signals to the surrounding cells. During CKD, the overriding insults can cause cell death of intrinsic kidney cells and immune cells and contribute to worse kidney outcomes. Inflammasomes are multi-protein complexes which regulate innate immune response and cell death called pyroptosis. We examined immune cell death in AKI and acute-on-chronic injury kidneys. Inflammasome formation and pyroptotic cell death in macrophages developed in the injured kidneys. We showed that a possible danger-associated molecular pattern (DAMP), double-stranded DNA, induced pyroptosis in kidney macrophages in the Aim2-dependent manner. We further demonstrated that many types of macrophages engaged in DNA-induced pyroptosis without releasing inflammasome-dependent cytokines. The differentiation status of dead macrophages seemingly determines the propagation of inflammation and contributes to the outcomes of acute-on-chronic kidney injury.

Academic Significance and Societal Importance of the Research Achievements

CKD腎という病的腎において、炎症細胞死の役割は未だ不明な点が多い。インフラマソームを介した炎症細胞死を制御することで、CKDの治療・進展予防に役立つ可能性がある。
本研究の成果により、二本鎖DNAが様々なマクロファージでパイロトーシスを誘導する可能性が示唆された。AKIおよびCKDは心血管病など様々な疾患の危険因子であり、有効な治療法が期待されている。CKD腎の炎症細胞死の重要性を示した本研究により、CKDのさらなる病態解明に向けて学術的・社会的な意義があると考えられる。

Report

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

    (12 results)

All 2022 2021 2020 Other

All Journal Article (8 results) (of which Peer Reviewed: 7 results,  Open Access: 5 results) Presentation (3 results) (of which Int'l Joint Research: 1 results) Remarks (1 results)

  • [Journal Article] dsDNA-induced AIM2 pyroptosis halts aberrant inflammation during rhabdomyolysis-induced acute kidney injury2022

    • Author(s)
      Baatarjav Chintogtokh、Komada Takanori、Karasawa Tadayoshi、Yamada Naoya、Sampilvanjil Ariunaa、Matsumura Takayoshi、Takahashi Masafumi
    • Journal Title

      Cell Death & Differentiation

      Volume: 29 Issue: 12 Pages: 2487-2502

    • DOI

      10.1038/s41418-022-01033-9

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cryo-sensitive aggregation triggers NLRP3 inflammasome assembly in cryopyrin-associated periodic syndrome2022

    • Author(s)
      Karasawa Tadayoshi、Komada Takanori、Yamada Naoya、Aizawa Emi、Mizushina Yoshiko、Watanabe Sachiko、Baatarjav Chintogtokh、Matsumura Takayoshi、Takahashi Masafumi
    • Journal Title

      eLife

      Volume: 11 Pages: 1-26

    • DOI

      10.7554/elife.75166

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Calciprotein Particles Induce IL-1β/α?Mediated Inflammation through NLRP3 Inflammasome-Dependent and -Independent Mechanisms2021

    • Author(s)
      Anzai Fumiya、Karasawa Tadayoshi、Komada Takanori、Yamada Naoya、Miura Yutaka、Sampilvanjil Ariunaa、Baatarjav Chintogtokh、Fujimura Kenta、Matsumura Takayoshi、Tago Kenji、Kurosu Hiroshi、Takeishi Yasuchika、Kuro-O Makoto、Takahashi Masafumi
    • Journal Title

      ImmunoHorizons

      Volume: 5 Issue: 7 Pages: 602-614

    • DOI

      10.4049/immunohorizons.2100066

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 横紋筋融解症による急性腎障害における DNA を介した炎症の制御2021

    • Author(s)
      駒田敬則, Chintogtokh Baatarjav, 高橋将文
    • Journal Title

      日本透析医会雑誌

      Volume: 36 Pages: 312-318

    • Related Report
      2021 Research-status Report
  • [Journal Article] NLRP3 Inflammasome Activation in Lung Vascular Endothelial Cells Contributes to Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury2020

    • Author(s)
      Ito Homare、Kimura Hiroaki、Karasawa Tadayoshi、Hisata Shu、Sadatomo Ai、Inoue Yoshiyuki、Yamada Naoya、Aizawa Emi、Hishida Erika、Kamata Ryo、Komada Takanori、Watanabe Sachiko、Kasahara Tadashi、Suzuki Takuji、Horie Hisanaga、Kitayama Joji、Sata Naohiro、Yamaji-Kegan Kazuyo、Takahashi Masafumi
    • Journal Title

      The Journal of Immunology

      Volume: 205 Issue: 5 Pages: 1393-1405

    • DOI

      10.4049/jimmunol.2000217

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] GSDME-Dependent Incomplete Pyroptosis Permits Selective IL-1α Release under Caspase-1 Inhibition2020

    • Author(s)
      Aizawa Emi、Karasawa Tadayoshi、Watanabe Sachiko、Komada Takanori、Kimura Hiroaki、Kamata Ryo、Ito Homare、Hishida Erika、Yamada Naoya、Kasahara Tadashi、Mori Yoshiyuki、Takahashi Masafumi
    • Journal Title

      iScience

      Volume: 23 Issue: 5 Pages: 101070-101070

    • DOI

      10.1016/j.isci.2020.101070

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] ASC regulates platelet activation and contributes to thrombus formation independent of NLRP3 inflammasome2020

    • Author(s)
      Watanabe Sachiko、Usui-Kawanishi Fumitake、Komada Takanori、Karasawa Tadayoshi、Kamata Ryo、Yamada Naoya、Kimura Hiroaki、Dezaki Katsuya、Ohmori Tsukasa、Takahashi Masafumi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 531 Issue: 2 Pages: 125-132

    • DOI

      10.1016/j.bbrc.2020.07.063

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Glucose regulates hypoxia-induced NLRP3 inflammasome activation in macrophages.2020

    • Author(s)
      1)Watanabe S, Usui-Kawanishi F, Karasawa, Kimura H, Kamata R, Inoue, Mise N, Kasahara T, Takahashi M
    • Journal Title

      J Cell Physiol

      Volume: - Issue: 10 Pages: 7554-7566

    • DOI

      10.1002/jcp.29659

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] Double-Stranded DNA-Induced AIM2 Pyroptosis Limits Excessive Inflammation During Rhabdomyolysis-Induced AKI2022

    • Author(s)
      Takanori Komada, Chintogtokh Baatarjav, Masafumi Takahashi
    • Organizer
      ASN(米国腎臓学会)Kidney week 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] AIM2-dependent pyroptosis is crucial for resolution after rhabdomyolysis-induced acute kidney injury(RIAKI)2021

    • Author(s)
      Chintogtokh Baatarjav, Takanori Komada, Masafumi Takahashi
    • Organizer
      the 64th Annual Meeting of the Japanese Society of Nephrology (JSN2021)
    • Related Report
      2021 Research-status Report
  • [Presentation] AIM2-dependent pyroptosis is crucial for resolution after rhabdomyolysis-induced acute kidney injury (RIAKI)2021

    • Author(s)
      Chintogtokh Baatarjav, Takanori Komada, Masafumi Takahashi
    • Organizer
      the 64th Annual Meeting of the Japanese Society of Nephrology (JSN2021)
    • Related Report
      2020 Research-status Report
  • [Remarks] 自治医科大学 分子病態研究センター 炎症・免疫研究部

    • URL

      https://www.jichi.ac.jp/inflammation/

    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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