Sustained Increases in Immune Transcripts and Immune Cell Trafficking During the Recovery of Experimental Brain Ischemia.
Sustained Increases in Immune Transcripts and Immune Cell Trafficking During the Recovery of Experimental Brain Ischemia.
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DOI：
10.1161/strokeaha.120.029440
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发表时间：
2020-08
期刊：
影响因子：
8.3
通讯作者：
Cho S
中科院分区：
文献类型：
--
作者：
Fury W;Park KW;Wu Z;Kim E;Woo MS;Bai Y;Macdonald LE;Croll SD;Cho S
中风是慢性神经功能障碍的主要原因。人们对了解急性转录组变化如何演变为促进或限制自发恢复的亚急性和慢性模式很感兴趣。在这里，我们绘制了小鼠中风后多个时间点基因表达的纵向变化至6个月。成年C57BL/6小鼠建立大脑中动脉一过性闭塞模型。在卒中后10个时间点，从缺血性卒中的急性期到恢复期，测定纵向转录组的水平。测定单核吞噬细胞在脑缺血后的定位和数量。对接受GFP+标记的脾细胞的脾小鼠进行整体脑成像。在卒中诱导的大脑半球，观察到持续的mRNA丰度变化，2989个同侧基因和822个对侧基因明显受到干扰。在梗塞同侧大脑半球，与免疫功能相关的基因受到强烈影响，包括时间重叠的先天免疫和获得性免疫以及巨噬细胞M1和M2表型相关基因。卒中急性期、亚急性期和恢复期免疫基因的强烈激活伴随着外周免疫细胞的持续浸润。卒中后2个月，梗死区可见浸润性免疫细胞，远隔区亦可见。研究发现，免疫成分是中枢神经系统损伤的主要分子特征，在中枢神经系统损伤后的亚急性期或慢性期，免疫成分可能对脑损伤产生增殖或持续的反应。这项研究提出了一种潜在的基于免疫的策略来改变缺血性中风的损伤进展和组织重塑，甚至在起始事件发生几个月后也是如此。脑缺血后免疫基因表达与免疫细胞存在的时空关系。M1和M2巨噬细胞基因图谱显示，在卒中的不同阶段，免疫相关基因的表达持续升高。免疫细胞转运主要发生在卒中急性期的原发损伤部位。中风慢性期偏远地区，包括丘脑和黑质(SN)的免疫细胞的存在，表明免疫参与了继发性损伤。
Stroke is a major cause of chronic neurological disability. There is considerable interest in understanding how acute transcriptome changes evolve into subacute and chronic patterns that facilitate or limit spontaneous recovery. Here we mapped longitudinal changes in gene expression at multiple time points after stroke in mice out to 6 months. Adult C57BL/6 mice were subjected to transient middle cerebral artery occlusion. Longitudinal transcriptome levels were measured at 10 time points after stroke from acute to recovery phases of ischemic stroke. Localization and the number of mononuclear phagocytes were determined in the post-ischemic brain. Whole mount brain imaging was performed in asplenic mice receiving GFP+-tagged splenocytes. Sustained stroke-induced mRNA abundance changes were observed in both hemispheres with 2989 ipsilateral and 822 contralateral genes significantly perturbed. In the hemisphere ipsilateral to the infarct, genes associated with immune functions were strongly affected, including temporally overlapping innate and adaptive immunity and macrophage M1 and M2 phenotype related-genes. The strong immune gene activation was accompanied by the sustained infiltration of peripheral immune cells at acute, subacute and recovery stages of stroke. The infiltrated immune cells were found in the infarcted area, but also in remote regions at 2 months after stroke. The study identifies that immune components are the predominant molecular signatures and they may propagate or continuously respond to brain injury in the subacute to chronic phase after CNS injury. The study suggests a potential immune-based strategy to modify injury progression and tissue remodeling in ischemic stroke, even months after the initiating event. The spatio-temporal relationship between immune gene expression and the presence of immune cells in the post-ischemic brain. M1 and M2 macrophage gene profiles showed sustained elevation of immune rassociated gene expression across different phases of stroke. Immune cell trafficking occurs mainly in the primary injury sites in the acute phase of stroke. The presence of immune cells during the chronic phase of stroke in remote areas, including the thalamus and substantia nigra (SN), shows an involvement of immunity in secondary injury.