Molecular mechanisms of NLRP3 inflammasome activation via glutathione efflux
Project/Area Number |
18H02098
|
Research Category |
Grant-in-Aid for Scientific Research (B)
|
Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
|
Research Institution | Kumamoto 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)
|
Keywords | NLRP3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)
Research Products
(15 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
Related 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
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
-
-
-
-
[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
Int'l Joint Research / Invited
-
-