Blocking Notch signal pathway suppresses the activation of neurotoxic A1 astrocytes after spinal cord injury
Blocking Notch signal pathway suppresses the activation of neurotoxic A1 astrocytes after spinal cord injury
复制标题
阻断Notch信号通路可抑制脊髓损伤后神经毒性A1星形胶质细胞的激活
DOI：
10.1080/15384101.2019.1667189
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发表时间：
2019-09-19
期刊：
影响因子：
4.3
通讯作者：
Yin, Guoyong
中科院分区：
文献类型：
--
作者：
Qian, Dingfei;Li, Linwei;Yin, Guoyong
脊髓损伤（Spinal Cord Injury，SCI）是一种严重的创伤性疾病，其发病机制复杂，包括炎症、氧化应激和胶质瘢痕形成。星形胶质细胞是中枢神经系统中数量最多的细胞，具有维持体内平衡的功能。最近的研究已经描述了一种新的星形胶质细胞反应表型，A1，由炎症诱导，这可能在SCI中有负面影响。由于Notch信号通路与细胞分化和炎症有关，我们旨在研究其在SCI星形胶质细胞分化中的潜在作用。损伤后28 d，损伤部位A1星形胶质细胞数量增加，Notch信号及其下游基因表达水平上调。Western blotting、RT-qPCR和免疫荧光检测显示，用γ-分泌酶阻断剂（DAPT）阻断Notch通路可抑制A1星形胶质细胞的分化。流式细胞术和TUNEL染色表明，DAPT可能通过Notch依赖性促炎因子的释放减轻A1星形胶质细胞引起的神经元凋亡和轴突损伤。CO-IP和Western blotting显示Notch信号通路与信号转导子和转录激活子3（Stat 3）相互作用，在A1星形胶质细胞分化中起重要作用。我们的结论是，A1星形胶质细胞的表型转变和它们的神经毒性是由Notch-Stat 3轴控制的，星形胶质细胞中的Notch通路可能作为一个有前途的治疗SCI的靶点。
ABSTRACT Spinal cord injury (SCI) is a catastrophic disease which has complicated pathogenesis including inflammation, oxidative stress and glial scar formation. Astrocytes are the most abundant cells in central nervous system and fulfill homeostatic functions. Recent studies have described a new reactive phenotype of astrocytes, A1, induced by inflammation, which may have negative effects in SCI. As the Notch signaling pathway has been linked to cell differentiation and inflammation, we aimed to investigate its potential role in the differentiation of astrocytes in SCI. Contusive SCI rat model showed elevated A1 astrocyte numbers at the damage site 28 days after SCI and the expression levels of Notch signaling and its downstream genes were upregulated parallelly. Western blotting, RT-qPCR and immunofluorescence revealed that blocking of Notch pathway using γ-secretase blocker (DAPT) suppressed the differentiation of A1 astrocytes. Flow cytometry, and TUNEL staining indicated that DAPT alleviated neuronal apoptosis and axonal damage caused by A1 astrocytes likely through the Notch-dependent release of pro-inflammatory factors. CO-IP and western blotting revealed an interaction between Notch pathway and signal transducer and activator of transcription 3 (Stat3), which played a vital role in differentiation of A1 astrocytes. We conclude that phenotypic transition of A1 astrocytes and their neurotoxity were controlled by the Notch-Stat3 axis and that Notch pathway in astrocytes may serve as a promising therapeutic target for SCI.