Molecular mechanisms of NLRP3 inflammasome activation via glutathione efflux

2020 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

細菌学、生化学

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。