The mechanism by which statins repress endogenous pathogenic crystal- or needle-like nanomaterial-induced inflammasome activation in macrophages

• Project/Area Number: 17K08406
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Environmental and hygienic pharmacy
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Nishimaki-Mogami Tomoko 国立医薬品食品衛生研究所, 生化学部, 客員研究員 (90174333)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: インフラマソーム / IL-1beta / NLRP3 / スタチン / コレステロール / カーボンナノチューブ / 薬学 / 脂質 / 炎症

Outline of Final Research Achievements

Endogenous and exogenous pathogenic crystals, such as cholesterol crystals, monosodium urate crystals, and asbestos-like multiwall carbon nanotubes (MWCNT) induce inflammasome activation in macrophages. We found that statins repress the crystal-stimulated the NLRP3 inflammasome activation and mature IL-1beta release by inhibiting the internalization of crystals. Various statins exerted the inhibition by decreasing prenyl-intermediates. The scavenger receptor MSR1 partly contributed to MWCNT-stimulated IL-1beta production and statins repressed the expression.

Academic Significance and Societal Importance of the Research Achievements

コレステロールや尿酸など内在性の結晶性異物によるNLRP3インフラマソーム活性化は、動脈硬化や痛風など慢性炎症の病態進展に深く関わる。本研究において、スタチンが顕著な抑制作用を示すことを発見するとともに、インフラマソームを介するスタチンの新しい抗炎症メカニズムが明らかになった。この成果は、MWCNTやアスベスト等の外来性異物が誘発する炎症病態の解明や治療薬創製、健康被害防止に道を拓くものと考えられる。

Research Products

• [Journal Article] Statins repress multi-wall carbon nanotube-stimulated IL-1b release through inhibiting the uptake by macrophages (2021)
  • Author(s): Nishimaki-Mogami T., Cui H., Soga K., Tamehiro N., Adachi R., Hachisuka A., Hirose A., Kondo K.
  • Journal Title: Toxicology Letters Volume: 350 Pages: S159-S160
  • DOI: 10.1016/s0378-4274(21)00617-2
  • Peer Reviewed
• [Journal Article] Statins repress needle-like carbon nanotube- or cholesterol crystal-stimulated IL-1β production by inhibiting the uptake of crystals by macrophages (2021)
  • Author(s): Cui Hongyan、Soga Keisuke、Tamehiro Norimasa、Adachi Reiko、Hachisuka Akiko、Hirose Akihiko、Kondo Kazunari、Nishimaki-Mogami Tomoko
  • Journal Title: Biochemical Pharmacology Volume: 188 Pages: 114580-114580
  • DOI: 10.1016/j.bcp.2021.114580
  • Peer Reviewed
• [Presentation] Statins repress multi-wall carbon nanotube-stimulated IL-1b release through inhibiting the uptake by macrophages (2021)
  • Author(s): Nishimaki-Mogami T, Cui H, Soga K, Tamehiro N, Adachi R, Hachisuka A, Hirose A, Kondo K
  • Organizer: EUROTOX 2021
  • Int'l Joint Research
• [Presentation] Statins repress cholesterol crystal-induced IL-1b production by decreasing the internalization of crystals by macrophages (2021)
  • Author(s): Nishimaki-Mogami T, Cui H, Soga K, Tamehiro N, Adachi R, Hachisuka A, Hirose A, Kondo K
  • Organizer: ISA 2021, The 19th International Symposium on Atherosclerosis
  • Int'l Joint Research
• [Presentation] 多層カーボンナノチューブによるIL-1β産生を抑制する化合物の同定 (2020)
  • Author(s): 最上(西巻)知子，崔 紅艶, 曽我慶介, 為広紀正, 安達玲子, 蜂須賀暁子, 広瀬明彦，近藤一成
  • Organizer: 第47回日本毒性学会学術年会
• [Presentation] Discovery of an inhibitor of multiwall carbon nanotubes-stimulated IL-1β secretion via inflammasome activation. (2019)
  • Author(s): Nishimaki-Mogami T, Cui H, Soga K, Adachi R, Tamehiro N, Hachisuka A, Kondo K, Hirose A
  • Organizer: EUROTOX 2019
  • Int'l Joint Research
• [Presentation] Identification of a sterol-responsive distal enhancer element for liver-specific ABCA1 gene expression. A novel mechanism for sterol-responsive hepatic ABCA1 gene regulation. (2019)
  • Author(s): Ohoka N, Cui H, Tamehiro H, Adachi R, Okuhira K, Naito M, Kondo K, Nishimaki-Mogami T
  • Organizer: HDL Workshop: Structure, novel functions, and therapeutic applications
  • Int'l Joint Research