Ischemic preconditioning induces cortical microglial proliferation and a transcriptomic program of robust cell cycle activation.
Ischemic preconditioning induces cortical microglial proliferation and a transcriptomic program of robust cell cycle activation.
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作者：
McDonough A;Noor S;Lee RV;Dodge R 3rd;Strosnider JS;Shen J;Davidson S;Möller T;Garden GA;Weinstein JR
缺血预处理（IPC）是一种实验现象，其中亚阈值缺血性损伤施加到脑中，以减少随后更严重的缺血发作所引起的损伤。确定IPC的关键分子和细胞介质将为开发卒中新疗法提供关键信息。在这里，我们报告说，急性分离的预处理的皮质小胶质细胞的转录组反应占主导地位的显着上调参与细胞周期激活和细胞增殖的基因。值得注意的是，这种转录反应发生在没有皮质梗死的情况下。我们采用离体流式细胞术、免疫荧光显微镜和定量体视学方法对脑组织进行了IPC后小胶质细胞增殖的评价。使用小胶质细胞（Iba 1）和增殖（Ki 67和BrdU）标记物的细胞共定位，我们观察到在IPC后72小时，而不是24小时，预处理的半皮质内的小胶质细胞和增殖小胶质细胞的数量局部增加。我们的定量结果表明，IPC诱导的总小胶质细胞的增加完全是由于增殖。此外，在预处理的大脑半球的小胶质细胞改变了形态和增加索马体积，表明一个激活的表型。使用Fractalkine受体（CX 3CR 1）-单倍不足或系统性I型干扰素信号转导缺失的转基因小鼠模型，我们确定IPC后小胶质细胞增殖依赖于Fractalkine信号转导，但独立于I型干扰素信号转导。这些发现表明，在小胶质细胞中存在多种不同的靶向信号通路，包括CX 3CR 1依赖性增殖，可能参与IPC介导的保护作用。
Ischemic preconditioning (IPC) is an experimental phenomenon in which a sub-threshold ischemic insult applied to the brain reduces damage caused by a subsequent more severe ischemic episode. Identifying key molecular and cellular mediators of IPC will provide critical information needed to develop novel therapies for stroke. Here we report that the transcriptomic response of acutely isolated preconditioned cortical microglia is dominated by marked up-regulation of genes involved in cell cycle activation and cellular proliferation. Notably, this transcriptional response occurs in the absence of cortical infarction. We employed ex vivo flow cytometry, immunofluorescent microscopy, and quantitative stereology methods on brain tissue to evaluate microglia proliferation following IPC. Using cellular co-localization of microglial (Iba1) and proliferation (Ki67 and BrdU) markers, we observed a localized increase in the number of microglia and proliferating microglia within the preconditioned hemicortex at 72, but not 24, hours post-IPC. Our quantification demonstrated that the IPC-induced increase in total microglia was due entirely to proliferation. Furthermore, microglia in the preconditioned hemisphere had altered morphology and increased soma volumes, indicative of an activated phenotype. Using transgenic mouse models with either fractalkine receptor (CX3CR1)-haploinsufficiency or systemic type I interferon signaling loss, we determined that microglial proliferation after IPC is dependent on fractalkine signaling but independent of type I interferon signaling. These findings suggest there are multiple distinct targetable signaling pathways in microglia, including CX3CR1-dependent proliferation, that may be involved in IPC-mediated protection.
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影响因子：
6.9
作者：
Bahjat FR;Alexander West G;Kohama SG;Glynn C;Urbanski HF;Hobbs TR;Earl E;Stevens SL;Stenzel-Poore MP
通讯作者：
Stenzel-Poore MP
影响因子：
32.4
作者：
Hammond, Timothy R.;Dufort, Connor;Stevens, Beth
通讯作者：
Stevens, Beth
影响因子：
6.3
作者：
Denes, Adam;Vidyasagar, Rishma;Allan, Stuart M.
通讯作者：
Allan, Stuart M.
影响因子：
8.3
作者：
Ejaz, Sohail;Emmrich, Julius V.;Baron, Jean-Claude
通讯作者：
Baron, Jean-Claude
DOI：
10.1073/pnas.95.18.10896
发表时间：
1998-09-01
影响因子：
11.1
作者：
Harrison, JK;Jiang, Y;Feng, LL
通讯作者：
Feng, LL