Roles of Prokineticin 2 in Subarachnoid Hemorrhage-Induced Early Brain Injury via Regulation of Phenotype Polarization in Astrocytes
Roles of Prokineticin 2 in Subarachnoid Hemorrhage-Induced Early Brain Injury via Regulation of Phenotype Polarization in Astrocytes
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Prokineticin 2 通过调节星形胶质细胞表型极化在蛛网膜下腔出血引起的早期脑损伤中的作用
DOI：
10.1007/s12035-020-01990-7
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发表时间：
2020-06-22
影响因子：
5.1
通讯作者：
Chen, Gang
中科院分区：
文献类型：
--
作者：
Ma, Mian;Li, Haiying;Chen, Gang
以前的研究假设神经炎症可以诱导两种不同类型的反应性星形胶质细胞，A1和A2。A1星形胶质细胞可能是有害的，而A2星形胶质细胞可能是保护性的。具体而言，前动力蛋白2（PK 2）已被证明通过促进星形胶质细胞中的替代A2保护表型来调节神经元-星形胶质细胞信号传导机制。本研究旨在探讨PK 2在蛛网膜下腔出血（SAH）引起的早期脑损伤（EBI）中的作用。SAH诱导的星形胶质细胞活化通过蛋白质印迹法证实。我们确认C3和PTX 3分别作为区分A1和A2星形胶质细胞的适当反应性标志物。我们还观察到SAH诱导的星形胶质细胞激活SAH患者。人和大鼠SAH后神经元中PK 2的增加表明PK 2与SAH病理学之间可能存在关系。PK 2敲低促进A1星形胶质细胞表型与神经退行性指标的上调，而血管内注射重组PK 2（rPK 2）促进A2星形胶质细胞表型和减少蛛网膜下腔出血诱导的神经元损伤和行为功能障碍。最后，我们确定肿瘤坏死因子α（TNF-α）足以提高神经元中PK 2的蛋白水平，并增强体外星形胶质细胞的活化。此外，rPK 2选择性地促进星形胶质细胞在TNF-α刺激下极化为A2表型，并诱导信号转导子和转录激活子3（STAT 3）的磷酸化，这表明SAH诱导的PK 2增加可能作为一种内源性自我修复机制。总的来说，我们的研究结果支持，增强PK 2的表达或管理的rPK 2可能会诱导选择性调节星形胶质细胞极化的保护性表型SAH样刺激后。
Previous studies have postulated that neuroinflammation can induce two different types of reactive astrocytes, A1 and A2. A1 astrocytes may be harmful, whereas A2 astrocytes may be protective. Specifically, prokineticin 2 (PK2) has been shown to regulate neuron-astrocyte signaling mechanism by promoting an alternative A2-protective phenotype in astrocytes. This study aimed to examine the role of PK2 in early brain injury (EBI) caused by subarachnoid hemorrhage (SAH). SAH-induced astrocytic activation was confirmed by Western blotting. We confirmed C3 and PTX3 as appropriate reactivity markers for discriminating A1 and A2 astrocytes, respectively. We also observed SAH-induced astrocytic activation in SAH patients. The increase of PK2 in neurons after SAH in both humans and rats suggested a possible relationship between PK2 and SAH pathology. PK2 knockdown promoted an A1 astrocytic phenotype with upregulation of neurodegenerative indicators, while intravascular injection of recombinant PK2 (rPK2) promoted A2 astrocytic phenotype and reduced SAH-induced neuronal injury and behavioral dysfunction. Finally, we identified that tumor necrosis factor alpha (TNF-alpha) was sufficient to elevate the protein level of PK2 in neurons and enhance astrocytic activation in vitro. Moreover, rPK2 selectively promoted astrocytic polarization to an A2 phenotype under a TNF-alpha stimulus and induced phosphorylation of signal transducer and activator of transcription 3 (STAT3), suggesting that SAH-induced increases in PK2 may function as an endogenous mechanism for self-repair. Collectively, our findings support that enhancing PK2 expression or administration of rPK2 may induce a selective modulation of astrocytic polarization to a protective phenotype following SAH-like stimuli.