Department of Neurosurgery, Xijing Hospital, Air Force Military Medical University, No. 127, Changle West Road, Xincheng District, Xi'an, 710032, Shaanxi, China.
J Neuroinflammation. 2022 Mar 14;19(1):67. doi: 10.1186/s12974-022-02428-8.
Inflammation induced by intracerebral hemorrhage (ICH) is one of the main causes of the high mortality and poor prognosis of patients with ICH. A1 astrocytes are closely associated with neuroinflammation and neurotoxicity, whereas A2 astrocytes are neuroprotective. Homer scaffolding protein 1 (Homer1) plays a protective role in ischemic encephalopathy and neurodegenerative diseases. However, the role of Homer1 in ICH-induced inflammation and the effect of Homer1 on the phenotypic conversion of astrocytes remain unknown.
Femoral artery autologous blood from C57BL/6 mice was used to create an ICH model. We use the A1 phenotype marker C3 and A2 phenotype marker S100A10 to detect astrocyte conversion after ICH. Homer1 overexpression/knock-down mice were constructed by adeno-associated virus (AAV) infection to explore the role of Homer1 and its mechanism of action after ICH. Finally, Homer1 protein and selumetinib were injected into in situ hemorrhage sites in the brains of Homer1/Nestin-Cre mice to study the efficacy of Homer1 in the treatment of ICH by using a mouse cytokine array to explore the potential mechanism.
The expression of Homer1 peaked on the third day after ICH and colocalized with astrocytes. Homer1 promotes A1 phenotypic conversion in astrocytes in vivo and in vitro. Overexpression of Homer1 inhibits the activation of MAPK signaling, whereas Homer1 knock-down increases the expression of pathway-related proteins. The Homer1 protein and selumetinib, a non-ATP competitive MEK1/2 inhibitor, improved the outcome in ICH in Homer1/Nestin-Cre mice. The efficacy of Homer1 in the treatment of ICH is associated with reduced expression of the inflammatory factor TNFSF10 and increased expression of the anti-inflammatory factors activin A, persephin, and TWEAK.
Homer1 plays an important role in inhibiting inflammation after ICH by suppressing the A1 phenotype conversion in astrocytes. In situ injection of Homer1 protein may be a novel and effective method for the treatment of inflammation after ICH.
脑内出血（ICH）引起的炎症是导致 ICH 患者死亡率高和预后不良的主要原因之一。A1 星形胶质细胞与神经炎症和神经毒性密切相关，而 A2 星形胶质细胞具有神经保护作用。 Homer 支架蛋白 1（Homer1）在缺血性脑病和神经退行性疾病中发挥保护作用。然而，Homer1 在 ICH 诱导的炎症中的作用以及 Homer1 对星形胶质细胞表型转化的影响尚不清楚。
使用 C57BL/6 小鼠的股动脉自体血建立 ICH 模型。我们使用 A1 表型标志物 C3 和 A2 表型标志物 S100A10 来检测 ICH 后星形胶质细胞的转化。通过腺相关病毒（AAV）感染构建 Homer1 过表达/敲低小鼠，以探讨 Homer1 的作用及其在 ICH 后的作用机制。最后，将 Homer1 蛋白和 selumetinib 注射到 Homer1/Nestin-Cre 小鼠脑内原位出血部位，通过小鼠细胞因子阵列研究 Homer1 治疗 ICH 的疗效，探讨潜在机制。
ICH 后第 3 天 Homer1 表达达到峰值，并与星形胶质细胞共定位。 Homer1 在体内和体外促进星形胶质细胞的 A1 表型转化。 Homer1 过表达抑制 MAPK 信号通路的激活，而 Homer1 敲低则增加通路相关蛋白的表达。 Homer1 蛋白和 selumetinib（一种非 ATP 竞争性 MEK1/2 抑制剂）可改善 Homer1/Nestin-Cre 小鼠 ICH 的预后。 Homer1 在治疗 ICH 中的疗效与炎症因子 TNFSF10 表达降低和抗炎因子 activin A、persephin 和 TWEAK 表达增加有关。
Homer1 通过抑制星形胶质细胞的 A1 表型转化，在 ICH 后抑制炎症反应中发挥重要作用。 Homer1 蛋白的原位注射可能是治疗 ICH 后炎症的一种新的有效方法。
