STAT6信号通路介导中性粒细胞极化和网捕死亡在缺血性卒中的作用

免疫损伤是急性缺血性卒中(AIS)神经功能恶化的重要机制之一。中性粒细胞是AIS后最早浸润大脑的外周免疫细胞，在级联炎症反应中具有N1和N2亚型两种极化状态，N1亚型通过释放含有大量促炎因子的胞外网捕死亡陷阱加剧神经炎症反应。然而，目前中性粒细胞在AIS中亚型极化和网捕死亡的发生机制不明。我们前期研究发现AIS后STAT6磷酸化水平下降伴随N1亚型中性粒细胞增多，推测STAT6信号通路可能调控中性粒细胞的亚型极化和网捕死亡，进而参与调节AIS的免疫炎症反应。为此，本课题以大脑中动脉栓塞动物模型和氧糖剥夺神经元与中性粒细胞共培养体系为体内、体外研究对象，进而探究：①中性粒细胞在AIS中亚型极化的动态变化及其对血脑屏障的免疫损伤；②STAT6信号通路对中性粒细胞亚型极化和网捕死亡的调控作用；③基于中性粒细胞亚型极化改善AIS的可行性，最终为AIS早期免疫炎症调控和神经保护提供新的治疗靶点。

Secondary immunoinflammation is one of mechanisms in the exaceration of acute ischemia stroke (AIS).Neutrophils are the first peripheral immune cells infiltrating into brain after AIS. They have two polarization states of N1 and N2 phenotypes with different surface markers and executive functions in the inflammatory cascade. N1 neutrophils exacerbate neural inflammation in the ischemic lesion via releasing neutrophil extracellular traps (NETs) which are large, web-like structures composed of cytosolic granule proteins and pro-inflammatory factors. However, the molecular mechanism that manipulates neutrophils phenotype polarization and NETs formation (also known as NETosis) in AIS remains to be explored. Our previous study found that post-stroke STAT6 phosphorylation was suppressed accompanying with increased N1 neutrophils polarization in the middle cerebral artery occlusion(MCAO) model, suggesting that STAT6 signaling pathway could be involved in post-stroke neuroinflammatory regulation. Hence, our study base on the MCAO model and neuron-neutrophil coculture system under oxygen sugar deprivation (OGD), aims to confirm that:①temporal and spatial dynamics of neutrophils phenotype polarization in AIS and corresponding immune effects to blood-brain barrier and oxygen glcouse deprivation neuron; ②molecular mechanism of STAT6 signaling pathway mediating neutrophil phenotype polarization and NETosis; ③feasibility of immune modulation strategy base on neutrophil phenotype plorazation in AIS neuroinflammation. Conclusively, the current study provides a promising therapeutic target based on neutrophils phenotype polarization regulation in AIS neuroprotection strategy.