TGFβ signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke.
TGFβ signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke.
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DOI：
10.1186/1742-2094-7-62
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发表时间：
2010-10-11
影响因子：
9.3
通讯作者：
Buckwalter MS
中科院分区：
文献类型：
--
作者：
Doyle KP;Cekanaviciute E;Mamer LE;Buckwalter MS
TGFβ 既具有神经保护作用，又是关键的免疫系统调节剂，很可能成为未来中风治疗的重要靶点。中风后增加的 TGF-β1 的确切功能尚不清楚，其多效性意味着它可以传递神经保护信号、协调神经胶质疤痕或作为重要的免疫系统调节剂。因此，我们研究了中风后 TGFβ 信号传导的时间进程和细胞特异性，以及其信号传导模式是否因性别和衰老而改变。我们对 5 个月和 18 个月大的 TGFβ 报告小鼠进行远端大脑中动脉闭塞中风，以实时读取中风后的 TGFβ 反应。为了确定哪种细胞类型是中风后 TGFβ 生成增加的来源，用抗 TGFβ 抗体对脑切片进行染色，并与反应性星形胶质细胞、神经元和激活的小胶质细胞的标记物共定位。为了确定中风后哪些细胞对 TGFβ 做出反应，脑切片用抗 pSmad2（TGFβ 信号传导标记物）以及神经元、少突胶质细胞、内皮细胞、星形胶质细胞和小胶质细胞标记物进行双重标记。中风后，TGFβ 信号传导增加 2 倍，从第 1 天开始，在第 7 天达到峰值。这种增加模式在老年动物中得以保留，并且大脑中的绝对 TGFβ 信号传导随着年龄的增长而增加。活化的小胶质细胞和巨噬细胞是中风后 TGFβ 增加的主要来源，星形胶质细胞和活化的小胶质细胞和巨噬细胞在中风后表现出 TGFβ 信号传导的显着上调。神经元和少突胶质细胞中的 TGFβ 信号传导没有发生明显变化。我们发现 TGFβ 信号随着年龄的增长而增加，星形胶质细胞、活化的小胶质细胞和巨噬细胞是响应中风后 TGFβ 增加而经历 TGFβ 信号增加的主要细胞类型。因此，中风后 TGFβ 的增加可能调节神经胶质疤痕的形成和对中风的免疫反应。
TGFβ is both neuroprotective and a key immune system modulator and is likely to be an important target for future stroke therapy. The precise function of increased TGF-β1 after stroke is unknown and its pleiotropic nature means that it may convey a neuroprotective signal, orchestrate glial scarring or function as an important immune system regulator. We therefore investigated the time course and cell-specificity of TGFβ signaling after stroke, and whether its signaling pattern is altered by gender and aging. We performed distal middle cerebral artery occlusion strokes on 5 and 18 month old TGFβ reporter mice to get a readout of TGFβ responses after stroke in real time. To determine which cell type is the source of increased TGFβ production after stroke, brain sections were stained with an anti-TGFβ antibody, colocalized with markers for reactive astrocytes, neurons, and activated microglia. To determine which cells are responding to TGFβ after stroke, brain sections were double-labelled with anti-pSmad2, a marker of TGFβ signaling, and markers of neurons, oligodendrocytes, endothelial cells, astrocytes and microglia. TGFβ signaling increased 2 fold after stroke, beginning on day 1 and peaking on day 7. This pattern of increase was preserved in old animals and absolute TGFβ signaling in the brain increased with age. Activated microglia and macrophages were the predominant source of increased TGFβ after stroke and astrocytes and activated microglia and macrophages demonstrated dramatic upregulation of TGFβ signaling after stroke. TGFβ signaling in neurons and oligodendrocytes did not undergo marked changes. We found that TGFβ signaling increases with age and that astrocytes and activated microglia and macrophages are the main cell types that undergo increased TGFβ signaling in response to post-stroke increases in TGFβ. Therefore increased TGFβ after stroke likely regulates glial scar formation and the immune response to stroke.
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