Activation of JAK/STAT3 restores NK-cell function and improves immune defense after brain ischemia

Stroke-induced immune suppression predisposes the host to infections and can contribute to high morbidity and mortality in stroke patients. Because ischemic stroke has a profound effect on the systemic immune response, which may explain the increased susceptibility of stroke patients to infection, an urgent need persists for a better understanding of mechanisms associated with immune suppression; new and effective treatments for stroke can then be identified. NK cells play a key role in early host defense against pathogens by killing infected cells and/or producing cytokines such as IFN-gamma. Because the phenotype and function of peripheral NK cells have been widely investigated in ischemic stroke, nCounter Inflammation Gene Array Analysis was used to build immune-related gene profiles of NK cells to comprehensively analyze the molecular signature of NK cells after ischemic brain injury. We observed distinct gene expression profiles reflecting different splenic NK-cell phenotypes and functional properties across the time course of transient middle cerebral artery occlusion (MCAO). Based on gene expression and pathway-network analysis, lower expression levels of signal transducer and activator of transcription-3 (STAT3) were observed in animals with MCAO compared with sham control animals. Genetic activation of STAT3 through the introduction of STAT3 clustered regularly interspaced short palindromic repeats (CRISPR) plasmid prevented the loss of NK-cell-derived IFN-gamma production after MCAO, together with reduced bacterial burden and mortality. Our data suggest that brain ischemia impairs NK-cell-mediated immune defense in the periphery, at least in part through the JAK-STAT3 pathway, which can be readdressed by modulating STAT3 activation status.

卒中诱导的免疫抑制使宿主易受感染，并可能导致卒中患者的高发病率和高死亡率。由于缺血性卒中对全身免疫反应有深远影响，这或许可以解释卒中患者对感染的易感性增加，因此迫切需要更好地理解与免疫抑制相关的机制；进而确定新的有效的卒中治疗方法。自然杀伤（NK）细胞通过杀伤受感染细胞和/或产生如干扰素 -γ等细胞因子，在宿主早期抵御病原体中起关键作用。由于外周NK细胞的表型和功能在缺血性卒中中已被广泛研究，采用nCounter炎症基因芯片分析来构建NK细胞的免疫相关基因图谱，以全面分析缺血性脑损伤后NK细胞的分子特征。我们观察到在大脑中动脉短暂闭塞（MCAO）的过程中，反映不同脾脏NK细胞表型和功能特性的独特基因表达图谱。基于基因表达和通路网络分析，与假手术对照动物相比，在MCAO动物中观察到信号转导和转录激活因子3（STAT3）的表达水平较低。通过引入STAT3成簇规律间隔短回文重复序列（CRISPR）质粒对STAT3进行基因激活，可防止MCAO后NK细胞产生干扰素 -γ的能力丧失，同时减少细菌负荷和死亡率。我们的数据表明，脑缺血损害外周NK细胞介导的免疫防御，至少部分是通过JAK - STAT3通路，可通过调节STAT3的激活状态来解决这一问题。