Department of Neurology, The First Affiliated Hospital of Fujian Medical University, 20 Chazhong Road, Fuzhou, 350000, Fujian, People's Republic of China.
Department of Neurosurgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China.
Inflammation. 2019 Apr;42(2):572-585. doi: 10.1007/s10753-018-0914-4.
Accumulating evidence indicates that post-injury inflammation characterized by activated microglia contributes much to the neuropathology of ischemic injury. Several studies have demonstrated that microglia exhibit two entirely different functional activation states, referred to as classically activated (M1) and alternatively activated (M2) phenotype. Promoting microglial phenotype to switch from M1 dominant to M2 dominant might be a promising approach for handling ischemic injury. However, the comprehensive mechanism that underlines microglia polarization in ischemic brain remains unclear. Neuronal erythropoietin-producing human hepatocellular carcinoma cell receptor 4 (EphA4), the richest Eph receptor in the central nervous system (CNS), upregulate after ischemia and may have the potential to regulate microglia activation. We hypothesized that modulating EphA4/ephrin signaling could affect ischemic injury through controlling microglia polarization. We therefore knocked down neuronal EphA4 with short hairpin RNA (shRNA) and determined the role of EphA4/ephrin signaling in oxygen-glucose deprivation and reperfusion (OGD/R)-induced injury. We found that EphA4 shRNA treatment attenuated OGD/R-induced apoptosis and microglia proliferation. Neuronal EphA4 knockdown also promoted microglial M2 polarization, which reduced pro-inflammatory mediators and released anti-inflammatory cytokines as well as neurotrophic factors. We further revealed that EphA4 shRNA treatment functioned through RhoA/Rho-associated kinase 2 (ROCK2) signaling, a key mediator of microglia alternative activation. Together, these data suggested that blockage of EphA4/ephrin signaling between neuron and microglia decreased OGD/R-induced injury by promoting alternative activation of microglia via RhoA/ROCK2 signaling.
越来越多的证据表明，以激活小胶质细胞为特征的损伤后炎症对缺血性损伤的神经病理学有很大影响。有几项研究表明，小胶质细胞表现出两种完全不同的功能激活状态，称为经典激活（M1）和交替激活（M2）表型。促进小胶质细胞表型从 M1 优势向 M2 优势转变可能是处理缺血性损伤的一种有前途的方法。然而，在缺血性大脑中小胶质细胞极化的综合机制仍不清楚。神经元促红细胞生成素产生的人肝癌细胞受体 4（EphA4）是中枢神经系统（CNS）中最丰富的 Eph 受体，在缺血后上调，并且可能具有调节小胶质细胞激活的潜力。我们假设调节 EphA4/ephrin 信号可能通过控制小胶质细胞极化来影响缺血性损伤。因此，我们用短发夹 RNA（shRNA）敲低神经元 EphA4，并确定 EphA4/ephrin 信号在氧葡萄糖剥夺和再灌注（OGD/R）诱导损伤中的作用。我们发现 EphA4 shRNA 处理可减轻 OGD/R 诱导的细胞凋亡和小胶质细胞增殖。神经元 EphA4 敲低也促进了小胶质细胞 M2 极化，从而减少了促炎介质的释放和抗炎细胞因子以及神经营养因子的释放。我们进一步揭示 EphA4 shRNA 处理通过 RhoA/Rho 相关激酶 2（ROCK2）信号发挥作用，这是小胶质细胞交替激活的关键介质。总之，这些数据表明，神经元和小胶质细胞之间 EphA4/ephrin 信号的阻断通过 RhoA/ROCK2 信号促进小胶质细胞的交替激活，从而减少 OGD/R 诱导的损伤。
