Erythropoietin ameliorates early brain injury after subarachnoid haemorrhage by modulating microglia polarization via the EPOR/JAK2-STAT3 pathway
Erythropoietin ameliorates early brain injury after subarachnoid haemorrhage by modulating microglia polarization via the EPOR/JAK2-STAT3 pathway
复制标题
促红细胞生成素通过 EPOR/JAK2-STAT3 通路调节小胶质细胞极化，改善蛛网膜下腔出血后的早期脑损伤
DOI：
10.1016/j.yexcr.2017.11.002
复制
发表时间：
2017-12-15
影响因子：
3.7
通讯作者：
Yi, Bin
中科院分区：
文献类型：
--
作者：
Wei, Shanwu;Luo, Chunxia;Yi, Bin
小胶质细胞M1/M2极化介导的炎症调节是蛛网膜下腔出血(SAH)后早期脑损伤(EBI)的主要病理生理过程之一。以往的研究表明，重组人促红细胞生成素(RhEPO)可减轻实验性蛛网膜下腔出血后的EBI。然而，这种有益效果的机制仍然知之甚少。最近的研究表明，促红细胞生成素具有抗炎作用。因此，我们试图分析重组人促红细胞生成素对蛛网膜下腔出血后早期脑损伤小胶质细胞M1/M2极化的影响，并确定其潜在的分子机制。我们发现，重组人促红细胞生成素治疗显著改善SAH诱导的EBI，表现为脑细胞凋亡、神经元坏死、白蛋白渗出和脑水肿的减少。此外，在SAH诱导后，p-JAK2和p-STAT3在大脑皮层的表达水平显著升高，EPO治疗后，p-JAK2和p-STAT3的表达水平进一步增加，另外，p-JAK2抑制剂AZD1480减弱了EPO对SAH诱导的EBI的保护作用。此外，EPO促进小胶质细胞向保护性M2表型的极化，减轻炎症。在氧合血红蛋白(OxyHb)处理的培养的小胶质细胞中，EPO上调EPO受体(EPOR)的表达，这不是OxyHb单独作用的结果，并且EPO放大了OxyHb诱导的p-JAK2和p-STAT3的增加，并调节了OxyHb挑战的小胶质细胞向M2的极化。有趣的是，EPO对小胶质细胞极化的影响被EPOR基因敲除或被p-JAK2或p-STAT3抑制所抵消，这表明EPOR/JAK2/STAT3通路在调节小胶质细胞的功能和表型中起着核心作用。结论：重组人促红细胞生成素对SAH后早期脑损伤的治疗作用可能与其调节炎症反应和小胶质细胞M1/M2极化有关，该作用部分通过EPOR/JAK2/STAT3信号通路实现。这些结果加深了对EPO对小胶质细胞极化的抗炎作用的认识，可能会优化EPO治疗SAH的治疗方式。
Inflammatory modulation mediated by microglial M1/M2 polarization is one of the main pathophysiological processes involved in early brain injury (EBI) after subarachnoid haemorrhage (SAH). Previous studies have shown that recombinant human erythropoietin (rhEPO) alleviates EBI following experimental SAH. However, the mechanisms of this beneficial effect are still poorly understood. Recent research has suggested that EPO shows anti-inflammatory properties. Therefore, we tried to analyse whether rhEPO administration influenced microglial M1/M2 polarization in early brain injury after SAH and to identify the underlying molecular mechanism of any such effect. We found that treatment with rhEPO markedly ameliorated SAH-induced EBI, as shown by reductions in brain cell apoptosis, neuronal necrosis, albumin exudation and brain edema. Moreover, the expression levels of p-JAK2 and p-STAT3 were significantly increased in the cortex after SAH induction and were further increased by EPO treatment; in addition, the p-JAK2 inhibitor AZD1480 impaired the protective effect of EPO against SAH-induced EBI in vivo. Furthermore, EPO promoted the polarization of microglia towards the protective M2 phenotype and alleviated inflammation. In cultured microglia under oxyhemoglobin (OxyHb) treatment, EPO up-regulated the expression of the EPO receptor (EPOR), which did not occur in response to OxyHb treatment alone, and EPO magnified OxyHb-induced increases in p-JAK2 and p-STAT3 and modulated OxyHb-challenged microglial polarization towards M2. Interestingly, the effect of EPO on microglia polarization was cancelled by EPOR knockdown or by p-JAK2 or p-STAT3 inhibition, suggesting a core role of the EPOR/JAK2/STAT3 pathway in modulating microglial function and phenotype. In conclusion, the therapeutic effect of rhEPO on the early brain injury after SAH may relate to its modulation of inflammatory response and microglia Ml/M2 polarization, which may be mediated in part by the EPOR/JAK2/STAT3 signalling pathway. These results improved the understanding of the anti-inflammatory effect of EPO on microglia polarization, which might optimize the therapeutic modalities of EPO treatment with SAH.