ASC contributes to thrombus formation independent of NLRP3

• Project/Area Number: 18K15900
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Jichi Medical University
• Principal Investigator: Watanabe Sachiko 自治医科大学, 医学部, 助教 (80770619)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 血小板 / 血栓症 / インフラマソーム / ASC

Outline of Final Research Achievements

NLRP3 inflammasome is a cytosolic multi-protein complex that regulates IL-1β maturation and plays a key role in sterile inflammatory diseases. ASC (apoptosis-associated speck-like protein containing a CARD) is an adaptor protein of NLRP3 inflammasome. In this study, we identified a candidate molecule that interacts with ASC. We also found that mouse platelets expressed only ASC, but not NLRP3 and caspase-1, suggesting NLRP3 inflammasome-independent role of ASC in the process of thrombosis. ASC-KO platelets displayed hyperactivation in response to GPVI agonists and this was associated with enhanced Ca2+ mobilization and integrin activation downstream of GPVI. Our results demonstrate that ASC negatively regulates GPVI signaling in platelets and enhances thrombus formation, independent of NLRP3 inflammasome. These findings provide novel insights into the mechanism of inflammation-related thrombosis and suggest that ASC is a novel potential therapeutic target for thrombosis.

Academic Significance and Societal Importance of the Research Achievements

本研究により、血小板においてASCがインフラマソームとは独立した作用で血栓形成機序に寄与していることが明らかになった。血小板凝集における新たな分子機構の解明、および本邦における心筋梗塞や脳梗塞といった血栓関連疾患の増加という点から、本研究の学術的・社会的な意義は大きいと考えられる。

Research Products

• [Journal Article] Glucose regulates hypoxia-induced NLRP3inflammasome activation in macrophages. (2020)
  • Author(s): Watanabe S, Usui-Kawanishi F, Karasawa T, Kimura H, Kamata R, InoueY, Mise N, Kasahara T, Takahashi M
  • Journal Title: Journal of Cellular Physiology Volume: －
  • Peer Reviewed / Open Access
• [Journal Article] Inflammasome-independent and atypical processing of IL-1β contributes to acid aspiration-induced acute lung injury. (2019)
  • Author(s): 5)Mizushina Y, Karasawa T, Aizawa K, Kimura H, Watanabe S, Kamata R, Komada T, Mato N, Kasahara T, Koyama S, Bando M, Hagiwara K, Takahashi M
  • Journal Title: J Immunol Volume: 203 Issue: 1 Pages: 236-246
  • DOI: 10.4049/jimmunol.1900168
  • Peer Reviewed / Open Access
• [Journal Article] Crucial role of NLRP3 inflammasome in the development of peritoneal dialysis-related peritoneal fibrosis. (2019)
  • Author(s): 6)Hishida E, Ito H, Komada T, Karasawa T, Kimura H, Watanabe S, Kamata R, Aizawa E, Kasahara T, Morishita Y, AkimotoT, Nagata D, Takahashi M
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 10363-10363
  • DOI: 10.1038/s41598-019-46504-1
  • Peer Reviewed / Open Access
• [Journal Article] Role of TLR5 in inflammation and tissue damage after intestinal ischemia-reperfusion injury. (2019)
  • Author(s): 7)Ito H, Sadatomo A, Inoue Y, Yamada N, Aizawa E, Hishida E, Kamata R, Karasawa T, Kimura H, Watanabe S, Komada T, Horie H, Kitagawa J, Sata N, Takahashi M
  • Journal Title: Biochem Biophys Res Commun Volume: 519 Issue: 1 Pages: 15-22
  • DOI: 10.1016/j.bbrc.2019.08.083
  • Peer Reviewed / Open Access
• [Presentation] 飽和脂肪酸は結晶形成を介して好中球浸潤を誘導する (2019)
  • Author(s): 唐澤直義、渡邊幸子、笠原忠、高橋将文
  • Organizer: 第51回日本動脈硬化学会総会・学術集会
• [Remarks] 自治医科大学 分子病態治療研究センター 炎症・免疫研究部
  • URL: http://www.jichi.ac.jp/inflammation/