All trans-retinoic acid protects against acute ischemic stroke by modulating neutrophil functions through STAT1 signaling
All trans-retinoic acid protects against acute ischemic stroke by modulating neutrophil functions through STAT1 signaling
复制标题
所有反式视黄酸均可通过 STAT1 信号传导调节中性粒细胞功能，从而预防急性缺血性中风
DOI：
10.1186/s12974-019-1557-6
复制
发表时间：
2019-08-31
影响因子：
9.3
通讯作者：
Zheng, Song Guo
中科院分区：
文献类型：
--
作者：
Cai, Wei;Wang, Julie;Zheng, Song Guo
背景和目的神经炎症的调节被认为是缺血性卒中的重要治疗靶点。全反式维甲酸(AtRA)是一种有效的免疫调节剂，在卒中治疗领域引起了人们的兴趣。然而，全反式维甲酸介导的神经保护的免疫学机制仍然不清楚。本研究旨在探讨全反式维甲酸(AtRA)对卒中后神经炎症的影响，并阐明其相关的中性粒细胞功能调节机制。方法在小鼠大脑中动脉短暂性闭塞(tMCAO，1h)前1d预防性应用atRA，再灌注后即刻每日重复给药，连续3d。评估卒中结果、中性粒细胞极化和卒中病变中中性粒细胞胞外陷阱(NETs)的形成。用抗Ly6G抗体诱导中性粒细胞耗竭。用原代培养的中性粒细胞来探讨atRA的治疗机制。结果预防性atRA治疗在tMCAO后1d减少了脑梗塞体积和神经功能缺失。卒中后神经炎症减轻，中性粒细胞在病变部位聚集下调。全反式维甲酸处理使中性粒细胞向N2型倾斜，促进其被巨噬细胞清除，并抑制Net的形成。中性粒细胞的功能在atRA的保护作用中是不可或缺的，并与atRA对STAT1信号的抑制有关。卒中后应用全反式维甲酸对脑缺血仍有有效的保护作用。结论全反式维甲酸通过减轻神经炎症，对缺血性卒中有较好的治疗作用。全反式维甲酸的治疗可阻止中性粒细胞聚集，有利于氮极化，并阻止缺血损伤中Net的形成。STAT1信号在全反式维甲酸对中性粒细胞的调节机制中起决定性作用。
Background and purposeRegulation of neural inflammation is considered as a vital therapeutic target in ischemic stroke. All-trans retinoic acid (atRA), a potent immune modulator, has raised interest in the field of stroke therapy. However, the immunological mechanisms for atRA-mediated neuroprotection remain elusive. The current study evaluated the impact of atRA on post-stroke neural inflammation and elucidated the mechanisms involved in the regulation of related neutrophil functions.MethodsatRA was prophylactically administered to mice 1 day before transient middle cerebral artery occlusion (tMCAO, 1 h) and repeated daily immediately after reperfusion for 3 days. Stroke outcomes, neutrophil polarization, and formation of neutrophil extracellular traps (NETs) in the stroke lesion were assessed. Neutrophil depletion was induced with anti-Ly6G antibodies. Primary neutrophil cultures were used to explore the mechanisms of atRA treatment.ResultsProphylactic atRA treatment reduced infarct volumes and neurological deficits at 1 day after tMCAO. Post-stroke neural inflammation was attenuated and neutrophil accumulation in lesion was downregulated. atRA treatment skewed neutrophil toward N2 phenotype which facilitated its clearance by macrophage and inhibited NETs formation. The functions of neutrophil were indispensable in the protective effects of atRA and were associated with suppression to STAT1 signaling by atRA. Administration of atRA after stroke still provided efficient protection to cerebral ischemia.ConclusionatRA displays potent therapeutic efficacy in ischemic stroke by attenuating neural inflammation. Treatment of atRA impeded neutrophil accumulation, favored N2 polarization, and forbade NETs formation in ischemic lesion. STAT1 signaling played a decisive role in the mechanisms of atRA-afforded regulation to neutrophil.