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-α) 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-α 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.

先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 星形胶质细胞可能有害，而 A2 星形胶质细胞可能具有保护作用。具体来说，前动力蛋白 2 (PK2) 已被证明可以通过促进星形胶质细胞中的另一种 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 PK2 在蛛网膜下腔出血 (SAH) 引起的早期脑损伤 (EBI) 中的作用。通过蛋白质印迹证实了 SAH 诱导的星形胶质细胞活化。我们确认 C3 和 PTX3 分别是区分 A1 和 A2 星形胶质细胞的适当反应标记。我们还在 SAH 患者中观察到 SAH 诱导的星形胶质细胞活化。人和大鼠 SAH 后神经元中 PK2 的增加表明 PK2 与 SAH 病理之间可能存在关系。 PK2敲除促进A1星形细胞表型，并上调神经退行性指标，而血管内注射重组PK2（rPK2）则促进A2星形细胞表型，并减少SAH引起的神经元损伤和行为功能障碍。最后，我们发现肿瘤坏死因子 α (TNF-α) 足以提高神经元中 PK2 的蛋白水平并增强体外星形胶质细胞的激活。此外，rPK2 在 TNF-α 刺激下选择性促进星形胶质细胞极化为 A2 表型，并诱导信号转导子和转录激活子 3 (STAT3) 磷酸化，表明 SAH 诱导的 PK2 增加可能作为自我修复的内源机制。 。总的来说，我们的研究结果支持增强 PK2 表达或施用 rPK2 可能会在 SAH 样刺激后诱导星形胶质细胞极化选择性调节至保护性表型。