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The role of caspase-11-dependent pyroptosis in atherosclerotic lesion

Research Project

Project/Area Number 21K06875
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49010:Pathological biochemistry-related
Research InstitutionJichi Medical University

Principal Investigator

Karasawa Tadayoshi  自治医科大学, 医学部, 講師 (60631893)

Co-Investigator(Kenkyū-buntansha) 高橋 将文  自治医科大学, 医学部, 教授 (40296108)
相澤 恵美  自治医科大学, 医学部, 助教 (80877621)
駒田 敬則  自治医科大学, 医学部, 講師 (90824730)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords炎症 / パイロトーシス / 動脈硬化 / 好中球 / カスパーゼ / 炎症性カスパーぜ / 炎症性カスパーゼ / インフラマソーム / マクロファージ / コレステロール結晶
Outline of Research at the Start

カスパーゼ11はカスパーゼ1と類似した酵素活性を示す炎症性カスパーゼとして知られており炎症性細胞死パイロトーシスの誘導とインフラマソームの活性化を引き起こす.本研究では,カスパーゼ11が脂質リガンドを直接認識し,動脈硬化病変における細胞死と炎症を制御するセンサー分子であるとの仮説の下,カスパーゼ11欠損が動脈硬化の進展に及ぼす影響を明らかにするとともに,動脈硬化病変におけるカスパーゼ11依存的な細胞死の誘導を検証する.さらに,カスパーゼ依存的な細胞死とコレステロール動態の関連を明らかにするため,パイロトーシスの過程におけるコレステロールがどのような制御を受けるかを明らかにする.

Outline of Final Research Achievements

Caspase-11 is an inflammatory caspase that triggers pyroptosis. However, the effect of caspase-11 deficiency on the development of atherosclerosis has not been fully evaluated. In the present study, we investigated the role of caspase-11 in the development of atherosclerosis. Apoe-deficient mice carrying caspase-11 mutation were fed a Western diet for 8 weeks. The formation of the necrotic core and deposition of cholesterol crystals are prevented by caspase-11 deficiency. The neutrophil infiltration into atherosclerotic lesions was also attenuated by caspase-11 deficiency. RNA-seq analysis revealed that upregulations of caspase-11 and neutrophil migration are common features of advanced atherosclerotic lesions. Furthermore, similar expression profiles were observed in unstable human plaque. These data suggest that caspase-11 regulates neutrophil recruitment and plaque destabilization in advanced atherosclerotic lesions.

Academic Significance and Societal Importance of the Research Achievements

心血管イベントの抑制には血中LDLコレステロールの低下だけでは不十分であることが明らかになってきており,この残余リスクを制御する標的として動脈硬化病変における炎症が注目されている.本研究成果は進展した動脈硬化病変においてカスパーゼ11が好中球の浸潤を制御することを明らかにした.炎症性カスパーゼが引き起こすパイロトーシスとそれに伴う好中球の浸潤は,今後,動脈硬化における炎症を制御し,心血管イベントを抑制する上での有効な標的として期待される.

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (7 results)

All 2023 2022 2021

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (2 results) (of which Invited: 1 results)

  • [Journal Article] Caspase-11 deficiency attenuates neutrophil recruitment into the atherosclerotic lesion in apolipoprotein E-deficient mice2023

    • Author(s)
      Karasawa Tadayoshi、Komada Takanori、Baatarjav Chintogtokh、Aizawa Emi、Mizushina Yoshiko、Fujimura Kenta、Gunji Yoshitaka、Komori Satoko、Aizawa Hidetoshi、Jing Tao Cantona Billton、Matsumura Takayoshi、Takahashi Masafumi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 686 Pages: 149158-149158

    • DOI

      10.1016/j.bbrc.2023.149158

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] NLRP3 inflammasome-driven IL-1β and IL-18 contribute to lipopolysaccharide-induced septic cardiomyopathy2023

    • Author(s)
      Fujimura Kenta、Karasawa Tadayoshi、Komada Takanori、Yamada Naoya、Mizushina Yoshiko、Baatarjav Chintogtokh、Matsumura Takayoshi、Otsu Kinya、Takeda Norihiko、Mizukami Hiroaki、Kario Kazuomi、Takahashi Masafumi
    • Journal Title

      Journal of Molecular and Cellular Cardiology

      Volume: 180 Pages: 58-68

    • DOI

      10.1016/j.yjmcc.2023.05.003

    • Related Report
      2023 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 Research-status Report
    • Peer Reviewed / Open Access
  • [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 Research-status 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
  • [Presentation] カスパーゼ11を介した好中球浸潤の制御と不安定プラーク形成との関連2023

    • Author(s)
      唐澤直義、駒田敬則、松村貴由、高橋将文
    • Organizer
      第55回日本動脈硬化学会総会・学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 脂肪酸によるNLRP3インフラマソームを介した炎症惹起機構と動脈硬化2021

    • Author(s)
      唐澤 直義
    • Organizer
      第53回日本動脈硬化学会総会・学術集会
    • Related Report
      2021 Research-status Report
    • Invited

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Published: 2021-04-28   Modified: 2025-01-30  

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