Elucidation of physiological roles of NLRP3 phosphorylation in the NLRP3 inflammasome formation

2019 Fiscal Year Final Research Report

• Project/Area Number: 16H05178
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nippon Medical School (2018-2019); Keio University (2016-2017)
• Principal Investigator: Morita Rimpei 日本医科大学, 大学院医学研究科, 大学院教授 (00362541)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 炎症 / マクロファージ / インフラマソーム / プログラム細胞死 / ミトコンドリア

Outline of Final Research Achievements

A pro-inflammatory cytokine IL-1b requires caspase-1 activation through NLRP3 inflammasome formation to be secreted extracellularly. We have previously reported that a non-receptor tyrosine kinase BTK is essential for NLRP3 inflammasome activation. At the beginning, in this study we had tried to determine amino acid residues of NLRP3 phosphorylated by BTK and to clarify its physiological significance. However, we met technical difficulties to purify a sufficient amount of phosphorylated NLRP3 for LC/LC-MS analysis and another research group reported the significance of phosphorylated NLRP3. Thus, we made an alternative of identifying a partner of NLRP3 in macrophages. As a result, we have found that an actin-modulating factor gelsolin negatively regulates NLRP3 inflammasome activation as well as apoptosis on the mitochondria.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

本研究によりgelsolinは細胞骨格アクチンを調整するのみならず、炎症性マクロファージのプログラム細胞死（pyroptosisとapoptosis）を抑制し生存を維持するユニークな因子であることが明らかになりつつある。これはいまだ不明である炎症環境下におけるマクロファージの生存維持が炎症反応の経過と組織修復に与える意義の解明につながる。感染症のみならずがんや生活習慣病にも炎症反応は必ず伴いその病態を修飾することから、本成果は多くの疾患の病態解明につながると期待される。