神经元-小胶质细胞EphA4/ephrin通路调控小胶质细胞介导的缺血后炎性损伤
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摘要
目的观察神经元-小胶质细胞间EphA4/ephrin信号通路在脑缺血后的炎性损伤中的作用及机制。方法建立神经元-小胶质细胞混合培养体系和糖氧剥夺再复氧(oxygen-glucose deprivation and reperfusion, OGD/R)模型,使用预聚集化的EphA4-Fc激动小胶质细胞ephrin配体,检测OGD/R后的细胞凋亡、小胶质细胞增殖和亚型极化以及小胶质细胞功能改变。结果 EphA4受体高表达于原代神经元,与对照组相比,预聚集化EphA4-Fc干预加重OGD/R导致的细胞凋亡,促进小胶质细胞增殖以及向M1型(促炎型)极化(炎症表型)。结论神经元-小胶质细胞间EphA4/ephrin信号通路通过调控小胶质细胞亚型极化参与脑缺血后的炎性损伤的过程。
Objective To investigate the role of neuron-microglia communication via EphA4/ephrin signaling pathway in inflammatory injury after ischemia and its mechanism. Methods Neuron-microglia co-culture system was constructed, as well as the oxygen-glucose deprivation and reperfusion(OGD/R) model was established. Pre-clustered EphA4-Fc was used as the agonist of microglial ephrin ligand. Then EphA4/ephrin signaling between neuron and microglia, namely OGD/R induced apotosis, microglial proliferation, polarization and function changes were analyzed. Results EphA4 receptor was highly expressed in primary neurons.Comparing to control group, pre-clustered EphA4-Fc intervention aggravated OGD/R-induced apoptosis as well as promoted microglial proliferation and its polarization to M1 type(inflammatory phenotype). Conclusion EphA4/ephrin signaling pathway between neuron and microglia was involved in the post-ischemic inflammatory injury by regulating polarization of microglia subtype.
Objective To investigate the role of neuron-microglia communication via EphA4/ephrin signaling pathway in inflammatory injury after ischemia and its mechanism. Methods Neuron-microglia co-culture system was constructed, as well as the oxygen-glucose deprivation and reperfusion(OGD/R) model was established. Pre-clustered EphA4-Fc was used as the agonist of microglial ephrin ligand. Then EphA4/ephrin signaling between neuron and microglia, namely OGD/R induced apotosis, microglial proliferation, polarization and function changes were analyzed. Results EphA4 receptor was highly expressed in primary neurons.Comparing to control group, pre-clustered EphA4-Fc intervention aggravated OGD/R-induced apoptosis as well as promoted microglial proliferation and its polarization to M1 type(inflammatory phenotype). Conclusion EphA4/ephrin signaling pathway between neuron and microglia was involved in the post-ischemic inflammatory injury by regulating polarization of microglia subtype.
引文
[1]Yang JS, Wei HX, Chen PP, et al. Roles of Eph/ephrin bidirectional signaling in central nervous system injury and recovery. Exp Ther Med, 2018, 15(3):2219-2227.
[2]Carmona MA, Murai KK, Wang L, et al. Glial ephrin-A3regulates hippocampal dendritic spine morphology and glutamate transport. Proc Natl Acad Sci USA, 2009, 106(30):12524-12529.
[3]Filosa A, Paixao S, Honsek SD, et al. Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamatetransport.NatNeurosci,2009,12(10):1285-1292.
[4]Murai KK, Nguyen LN, Irie F, et al. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nat Neurosci, 2003, 6(2):153-160.
[5]Yang J, Luo X, Huang X, et al. Ephrin-A3 reverse signaling regulates hippocampal neuronal damage and astrocytic glutamate transport after transient global ischemia. J Neurochem, 2014, 131(3):383-394.
[6]Ma Y, Wang J, Wang Y, Yang GY. The biphasic function of microglia in ischemic stroke. Prog Neurobiol, 2017, 157:247-272.
[7]Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia:the good, the bad, and the inflamed.J Neuroinflammation, 2014, 11:98.
[8]Hu X, Leak RK, Shi Y, et al. Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol,2015, 11(1):56-64.
[9]Hu X, Li P, Guo Y, et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke, 2012, 43(11):3063-3070.
[10] MunroKM,Perreau VM, Turnley AM.Differentialgene expression in the EphA4 knockout spinal cord and analysis of the inflammatory response following spinal cord injury.PLoS One, 2012, 7(5):e37635.
[11] Woodruff TM, Wu MC, Morgan M, et al. Epha4-Fc TreatmentReducesIschemia/Reperfusion-InducedIntestinal Injury by Inhibiting Vascular Permeability. Shock, 2016,45(2):184-191.
[2]Carmona MA, Murai KK, Wang L, et al. Glial ephrin-A3regulates hippocampal dendritic spine morphology and glutamate transport. Proc Natl Acad Sci USA, 2009, 106(30):12524-12529.
[3]Filosa A, Paixao S, Honsek SD, et al. Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamatetransport.NatNeurosci,2009,12(10):1285-1292.
[4]Murai KK, Nguyen LN, Irie F, et al. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nat Neurosci, 2003, 6(2):153-160.
[5]Yang J, Luo X, Huang X, et al. Ephrin-A3 reverse signaling regulates hippocampal neuronal damage and astrocytic glutamate transport after transient global ischemia. J Neurochem, 2014, 131(3):383-394.
[6]Ma Y, Wang J, Wang Y, Yang GY. The biphasic function of microglia in ischemic stroke. Prog Neurobiol, 2017, 157:247-272.
[7]Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia:the good, the bad, and the inflamed.J Neuroinflammation, 2014, 11:98.
[8]Hu X, Leak RK, Shi Y, et al. Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol,2015, 11(1):56-64.
[9]Hu X, Li P, Guo Y, et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke, 2012, 43(11):3063-3070.
[10] MunroKM,Perreau VM, Turnley AM.Differentialgene expression in the EphA4 knockout spinal cord and analysis of the inflammatory response following spinal cord injury.PLoS One, 2012, 7(5):e37635.
[11] Woodruff TM, Wu MC, Morgan M, et al. Epha4-Fc TreatmentReducesIschemia/Reperfusion-InducedIntestinal Injury by Inhibiting Vascular Permeability. Shock, 2016,45(2):184-191.