Novel therapeutic strategy for arterial thrombosis by targeting neutrophil extracellular trap formation in socially defeated mice

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08081
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Yamada Hiroyuki 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (00240036)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 好中球 / 好中球細胞外トラップ / うつ病 / 心血管病 / 血栓形成

Outline of Final Research Achievements

We investigated the impact of repeated social defeat (RSD) on arterial thrombosis in mice. Carotid arterial thrombosis was induced by FeCl3 application. The volume of occlusive thrombi was comparable between the defeated and control mice; however, fibrinogen/fibrin-positive areas was significantly increased in defeated mice. Further, Ly-6G-positive cells in defeated mice were co-localized with neutrophil elastase, Cit-H3, and CD42b-positive staining, suggesting that neutrophil extracellular traps (NETs) formation was enhanced in defeated mice. Treatment with DNase I completely diminished the exaggerated fibrin-rich clot formation in defeated mice. In vitro NETs formation assessed by Cit-H3/MPO double-positive cells was significantly higher in neutrophils of defeated mice. Our findings demonstrate that RSD enhances fibrin-rich clot formation after arterial injury by enhancing NETs formation, suggesting that NETosis could be a new therapeutic target in depression-related CVD development.

Free Research Field

動脈硬化

Academic Significance and Societal Importance of the Research Achievements

鬱病は心血管病発症の独立した危険因子であることが明らかとなってきたが、その機序は十分解明されていない。申請者らのグループは以前、鬱病モデルマウスにおいて惹起された骨髄由来免疫抑制細胞が、好中球細胞外トラップ形成（NETs）形成を介して動脈硬化形成促進に作用することを初めて報告したが、鬱病における心血管病発症機序を直接解析した報告はない。今回、鬱病モデルマウスを用いて「動脈血栓形成モデル」を作製し、NETs形成が動脈血栓形成に直接関与することを明らかにした。心血管病予防の新たな治療標的に発展させる可能性を示した点において意義深いと考える。