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Molecular mechanisms of NLRP3 inflammasome activation via glutathione efflux

Research Project

Project/Area Number 18H02098
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
Research InstitutionKumamoto University

Principal Investigator

Sawa Tomohiro  熊本大学, 大学院生命科学研究部(医), 教授 (30284756)

Co-Investigator(Kenkyū-buntansha) 津々木 博康  熊本大学, 大学院生命科学研究部(医), 助教 (40586608)
小野 勝彦  熊本大学, 大学院生命科学研究部(医), 助教 (80573592)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2020: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
KeywordsNLRP3インフラマソーム / グルタチオン / 超硫黄分子 / レドックス / 自然炎症 / インフラマソーム / 活性酸素 / 自然免疫
Outline of Final Research Achievements

NLRP3 inflammasome involves in host defense and inflammatory responses through maturation of precursor forms of interleukin-1beta into active proinflammatory cytokines and initiation of pyroptosis. This study was conducted to clarify the impact of cellular glutathione (GSH) towards NLRP3 inflammasome activation. We found that ATP induces rapid GSH decline in LPS-primed macrophages. Simultaneously, comparable level of GSH was detected in culture supernatants, suggesting ATP induced GSH efflux. Moreover, exogenous addition of GSH or oxidized form of GSH (GSSG) attenuated this GSH efflux. Importantly, activation of the NLRP3 inflammasome both in vitro and in vivo were strongly inhibited by adding GSH or GSSG extracellularly. These data suggest that GSH efflux triggers NLRP3 inflammasome activation, and hence constitute a potential therapeutic strategy for NLRP3 inflammasome-associated inflammatory disorders.

Academic Significance and Societal Importance of the Research Achievements

NLRP3インフラマソームの慢性的な活性化はクリオピリン関連周期熱症候群や痛風、さらにはごく最近では新型コロナウイルス感染症の重症化に関わることが報告されている。効果的な治療法の検討が進められている中で、今回の成果は、NLRP3インフラマソームの新しい活性化経路を明らかにしたことで、今後、それを標的とした新しい治療薬の探索や、感受性宿主の同定など、に大きく寄与することが期待される。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (15 results)

All 2021 2020 2019 2018

All Journal Article (9 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 9 results,  Open Access: 9 results) Presentation (6 results) (of which Int'l Joint Research: 1 results,  Invited: 3 results)

  • [Journal Article] ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation.2021

    • Author(s)
      Zhang, T., Tsutsuki, H., Islam, W., Ono, K., Takeda, K., Akaike, T. and Sawa, T.
    • Journal Title

      Redox Biology

      Volume: 41 Pages: 101930-101930

    • DOI

      10.1016/j.redox.2021.101930

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Preparation of Biodegradable PLGA-Nanoparticles Used for pH-Sensitive Intracellular Delivery of an Anti-inflammatory Bacterial Toxin to Macrophages2020

    • Author(s)
      Harada Ayaka、Tsutsuki Hiroyasu、Zhang Tianli、Lee Ruda、Yahiro Kinnosuke、Sawa Tomohiro、Niidome Takuro
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 68 Issue: 4 Pages: 363-368

    • DOI

      10.1248/cpb.c19-00917

    • NAID

      130007824942

    • ISSN
      0009-2363, 1347-5223
    • Year and Date
      2020-04-01
    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Enzymatic Regulation and Biological Functions of Reactive Cysteine Persulfides and Polysulfides2020

    • Author(s)
      Sawa Tomohiro、Motohashi Hozumi、Ihara Hideshi、Akaike Takaaki
    • Journal Title

      Biomolecules

      Volume: 10 Issue: 9 Pages: 1245-1245

    • DOI

      10.3390/biom10091245

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Synthesis of Pegylated Manganese Protoporphyrin as a Catalase Mimic and Its Therapeutic Application to Acetaminophen-Induced Acute Liver Failure2019

    • Author(s)
      Zhang Tianli、Fang Jun、Tsutsuki Hiroyasu、Ono Katsuhiko、Islam Waliul、Sawa Tomohiro
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 7 Pages: 1199-1206

    • DOI

      10.1248/bpb.b19-00152

    • NAID

      130007672166

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-07-01
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enhanced Cellular Polysulfides Negatively Regulate TLR4 Signaling and Mitigate Lethal Endotoxin Shock2019

    • Author(s)
      Zhang Tianli、Ono Katsuhiko、Tsutsuki Hiroyasu、Ihara Hideshi、Islam Waliul、Akaike Takaaki、Sawa Tomohiro
    • Journal Title

      Cell Chemical Biology

      Volume: in press Issue: 5 Pages: 686-698.e4

    • DOI

      10.1016/j.chembiol.2019.02.003

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Polysulfide stabilization by tyrosine and hydroxyphenyl-containing derivatives that is important for a reactive sulfur metabolomics analysis.2019

    • Author(s)
      Hamid HA, Tanaka A, Ida T, Nishimura A, Matsunaga T, Fujii S, Morita M, Sawa T, Fukuto JM, Nagy P, Tsutsumi R, Motohashi H, Ihara H, Akaike T.
    • Journal Title

      Redox Biol

      Volume: 21 Pages: 101096-101096

    • DOI

      10.1016/j.redox.2019.101096

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Persulfide synthases that are functionally coupled with translation mediate sulfur respiration in mammalian cells.2019

    • Author(s)
      Fujii S, Sawa T, Motohashi H, Akaike T.
    • Journal Title

      Br J Pharmacol

      Volume: 176 Issue: 4 Pages: 607-615

    • DOI

      10.1111/bph.14356

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Reactive Persulfides from Salmonella Typhimurium Downregulate Autophagy-Mediated Innate Immunity in Macrophages by Inhibiting Electrophilic Signaling2018

    • Author(s)
      Khan Shahzada、Fujii Shigemoto、Matsunaga Tetsuro、Nishimura Akira、Ono Katsuhiko、Ida Tomoaki、Ahmed Khandaker Ahtesham、Okamoto Tatsuya、Tsutsuki Hiroyasu、Sawa Tomohiro、Akaike Takaaki
    • Journal Title

      Cell Chemical Biology

      Volume: 25 Issue: 11 Pages: 1403-1413

    • DOI

      10.1016/j.chembiol.2018.08.007

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Reactive Cysteine Persulphides: Occurrence, Biosynthesis, Antioxidant Activity, Methodologies, and Bacterial Persulphide Signalling2018

    • Author(s)
      Sawa Tomohiro、Ono Katsuhiko、Tsutsuki Hiroyasu、Zhang Tianli、Ida Tomoaki、Nishida Motohiro、Akaike Takaaki
    • Journal Title

      Advances in Microbial Physiology

      Volume: 72 Pages: 1-28

    • DOI

      10.1016/bs.ampbs.2018.01.002

    • ISBN
      9780128144138
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 活性硫黄による自然炎症の制御機構2020

    • Author(s)
      澤 智裕
    • Organizer
      第47回日本毒性学会学術年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 細菌のシステイン合成酵素阻害剤の探索とその抗菌作用2020

    • Author(s)
      澤 智裕
    • Organizer
      第93回日本細菌学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 活性イオウによるNLRP3インフラマソームのレドックス調節機構2020

    • Author(s)
      澤 智裕
    • Organizer
      第19回分子予防環境医学研究会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] N-Acetyl-L-cysteine polysulfides act as potent polysulfide donors and mitigate lethal endotoxin shock via their anti-inflammatory effects.2019

    • Author(s)
      Zhang, T., Ono, K., Tsutsuki, H., Ihara, H., Islam, W., Akaike, T., Sawa, T.
    • Organizer
      The 9th Biennial Meeting of Society for Free Radical Research-Asia
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] システインパースルフィドを介した酸化ストレス防御機構の発見2018

    • Author(s)
      澤 智裕
    • Organizer
      第71回日本酸化ストレス学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] .活性イオウによる自然免疫応答の制御機構2018

    • Author(s)
      澤 智裕,張 田力,津々木博康,小野勝彦
    • Organizer
      第45回日本毒性学会学術集会
    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2023-12-25  

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