巨细胞DNase限制了神经细胞外细胞陷介导的动脉样硬化中有缺陷的细胞形成
Umesh Kumar Dhawan1, Tanwi Vartak2, Hanna Englert3
1William Harvey Research Institute, Queen Mary University of London, United Kingdom (U.K.D., S.R., A.S., K.K.B., M.S.).
Circulation research
|October 1, 2025
概括
由于巨细胞功能障碍导致的动脉样硬化中中性粒细胞外细胞陷 (NETs) 的清除受损,促进了斑块的进展. 通过准PERK-ATF4通路恢复DNase分泌,可以增强NET清除和斑块稳定.
科学领域:
- 心血管生物学 心血管生物学
- 免疫学 免疫学 免疫学
- 分子医学是分子医学.
背景情况:
- 中性细胞外细胞陷 (NETs) 与动脉样硬化和心血管不良事件有关.
- 人们对NET清除及其在动脉样硬化中破坏的机制知之甚少.
- 缺陷的NET清除对疾病进展的后果仍然未知.
研究的目的:
- 研究DNase活性和NET清除在动脉样硬化中的作用.
- 为了检查NETs对巨细胞的影响.
- 在动脉样硬化中确定调节DNase分泌和NET清除的信号通路.
主要方法:
- 使用低密度脂蛋白受体淘汰赛小鼠食西方饮食.
- 评估了DNase1和DNase1L3.3的造血细胞特异缺失.
- 在体外和体内体内检查了巨细胞的效细胞化.
- 采用内质网膜应激通路抑制剂来识别信号通路.
主要成果:
- 巨细胞DNase缺乏导致了在动脉样硬化斑块中的NET积累.
- NETs促进了MerTK裂变,损害了巨细胞的效和增加了斑块亡.
- 在巨细胞中由内质网膜压力诱导的PERK-ATF4信号传递导致DNase分泌受损和NET持久性.
- 在小鼠和人类组织中,PERK抑制恢复了DNase分泌和NET清除.
结论:
- 巨细胞对于NET清除至关重要.
- 细胞内膜网膜应激损害了巨细胞的DNase分泌,导致NET积累和细胞缺陷.
- 针对PERK-ATF4轴提供了通过恢复NET清除来稳定斑块的治疗策略.
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