FFAR2+中性粒细胞与大动脉粥样硬化型卒中的关联及其在血栓形成中的作用
The association of FFAR2+ neutrophils with large artery atherosclerotic stroke and their role in thrombosis
芮宇 1刘慧慧1
作者信息
- 1. 苏州大学附属第二医院神经内科，苏州 215004
- 折叠
摘要
目的：本研究旨在描绘急性缺血性卒中（Acute ischemic stroke，AIS）血栓的细胞异质性，并探讨游离脂肪酸受体2（Free Fatty Acid Receptor 2，FFAR2）在大动脉粥样硬化（Large artery atherosclerosis，LAA）相关血栓形成中的作用。方法：对AIS患者取出的血栓进行单细胞RNA测序（Single cell RNA sequencing，scRNA-seq）。分析细胞组成及转录组特征，鉴定并定量FFAR2+中性粒细胞。通过体外中性粒细胞胞外陷阱（Neutrophil extracellular traps，NETs）形成实验及三氯化铁（Ferric chloride，FeCl3）诱导的小鼠血栓模型，评估FFAR2的功能意义。利用激动剂丙酸钠和拮抗剂GLPG0974调控FFAR2活性。结果：scRNA-seq共鉴定出7种有核细胞类型，其中包括一个FFAR2表达升高的独特中性粒细胞亚群（NEU3）。与心源性栓塞（Cardioembolism，CE）血栓相比，LAA血栓中FFAR2+中性粒细胞显著富集，且其丰度与LAA型AIS患者基线美国国立卫生研究院卒中量表（National Institutes of health Stroke Scale, NIHSS）评分呈正相关。FFAR2激活可增强体外NETs形成，而拮抗剂抑制则能阻断这一反应。在体内，FFAR2激动促进中性粒细胞募集和血栓增长，而GLPG0974可逆转上述效应。结论：我们的单细胞图谱鉴定出一个促血栓形成的FFAR2+中性粒细胞亚群，该亚群在LAA型卒中中富集，并与疾病严重程度相关。FFAR2激活可促进NETs及血栓形成，提示FFAR2信号通路是血栓形成的关键介质及潜在治疗靶点。
Abstract
Objective: This study aimed to delineate the cellular heterogeneity of thrombi in acute ischemic stroke (AIS) and investigate the role of Free Fatty Acid Receptor 2 (FFAR2) in LAA-related thrombosis.Methods: Single-cell RNA sequencing (scRNA-seq) was performed on thrombi retrieved from AIS patients. Cellular composition and transcriptomic profiles were analyzed, identifying and quantifying of FFAR2+ neutrophils. The functional significance of FFAR2 was assessed using in vitro assays of neutrophil extracellular traps (NETs) formation and a ferric chloride (FeCl3)-induced murine thrombosis model. FFAR2 activity was modulated using the agonist sodium propionate and the antagonist GLPG0974. Results: scRNA-seq revealed seven nucleated cell types, including a distinct neutrophil subset (NEU3) with elevated FFAR2 expression. FFAR2+ neutrophils were significantly enriched in LAA thrombi compared with cardioembolic (CE) thrombi, and correlated with higher baseline National Institutes of Health Stroke Scale (NIHSS) scores in LAA-type AIS.FFAR2 activation enhanced NETs formation (NETosis) in vitro, while pharmacologic inhibition suppressed this response. In vivo, FFAR2 agonism promoted neutrophil recruitment and thrombus growth, effects reversed by GLPG0974. Conclusion: Our single-cell atlas identifies a prothrombotic FFAR2+ neutrophil subset enriched in LAA stroke and linked to disease severity. FFAR2 activation promotes NETosis and thrombus formation, highlighting FFAR2 signaling as a key mediator of thrombosis and potential therapeutic target.关键词
神经病学/急性缺血性卒中/动脉血栓/单细胞测序/中性粒细胞/FFAR2Key words
Neurology/Acute ischemic stroke/Arterial thrombosis/Single-cell sequencing/Neutrophils/FFAR2引用本文复制引用
芮宇,刘慧慧.FFAR2+中性粒细胞与大动脉粥样硬化型卒中的关联及其在血栓形成中的作用[EB/OL].(2026-04-08)[2026-04-11].http://www.paper.edu.cn/releasepaper/content/202604-69.学科分类
神经病学、精神病学/医学研究方法
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