EphrinB/EphB forward signaling in Müller cells causes apoptosis of retinal ganglion cells by increasing tumor necrosis factor alpha production in rat experimental glaucomatous model.
EphrinB/EphB forward signaling in Müller cells causes apoptosis of retinal ganglion cells by increasing tumor necrosis factor alpha production in rat experimental glaucomatous model.
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Müller 细胞中的 EphrinB/EphB 正向信号通过增加大鼠实验性青光眼模型中肿瘤坏死因子 α 的产生导致视网膜神经节细胞凋亡
DOI：
10.1186/s40478-018-0618-x
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发表时间：
2018-10-24
影响因子：
7.1
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Liu ST;Zhong SM;Li XY;Gao F;Li F;Zhang ML;Zhu K;Sun XH;Wang X;Miao Y;Yang XL;Wang Z
先前的研究表明，在大鼠慢性高眼压（COH）模型中，视网膜神经节细胞（RGCs）中的EphB/ephrinB反向信号被激活并参与RGC凋亡。在本研究中，我们首先发现ephrinB/EphB正向信号通路在COH视网膜中被激活，并且PP2（一种ephrinB/EphB正向信号通路抑制剂）可以减少COH视网膜中RGC的凋亡。我们进一步证明，用EphB1激活剂ephrinB1-Fc或在正常大鼠玻璃体内注射ephrinB1-Fc处理培养的<s:1> ller细胞，可诱导这些细胞磷酸化EphB水平的增加，表明ephrinB/EphB正向信号通路的激活，类似于COH视网膜。ephrinB1-Fc处理后，GFAP表达未发生变化，未诱导大鼠<s:2> ller细胞胶质化，但显著上调大鼠<s:2> ller细胞中肿瘤坏死因子-α (TNF-α) mRNA和蛋白水平，促进RGC凋亡。ephrinB/EphB正向信号激活诱导TNF-α的产生是由NMDA受体NR2B亚基介导的，随后是不同的PI3K/Akt/NF-κB信号通路，该通路的每一步的药物干扰都导致TNF-α的产生减少，从而减轻RGC凋亡。在这样一个独特的系统中，ephrin和Eph分别存在于胶质元件和神经元元件中，分析其正向和反向信号的功能具有重要的理论意义。此外，我们的研究结果还提出了抑制ephrinB/EphB正向信号传导可能是改善青光眼RGC凋亡的新策略。
It was previously shown that EphB/ephrinB reverse signaling in retinal ganglion cells (RGCs) is activated and involved in RGC apoptosis in a rat chronic ocular hypertension (COH) model. In the present work, we first show that ephrinB/EphB forward signaling was activated in COH retinas, and RGC apoptosis in COH retinas was reduced by PP2, an inhibitor of ephrinB/EphB forward signaling. We further demonstrate that treatment of cultured Müller cells with ephrinB1-Fc, an EphB1 activator, or intravitreal injection of ephrinB1-Fc in normal rats induced an increase in phosphorylated EphB levels in these cells, indicating the activation of ephrinB/EphB forward signaling, similar to those in COH retinas. The ephrinB1-Fc treatment did not induce Müller cell gliosis, as evidenced by unchanged GFAP expression, but significantly up-regulated mRNA and protein levels of tumor necrosis factor-α (TNF-α) in Müller cells, thereby promoting RGC apoptosis. Production of TNF-α induced by the activation of ephrinB/EphB forward signaling was mediated by the NR2B subunit of NMDA receptors, which was followed by a distinct PI3K/Akt/NF-κB signaling pathway, as pharmacological interference of each step of this pathway caused a reduction of TNF-α production, thus attenuating RGC apoptosis. Functional analysis of forward and reverse signaling in such a unique system, in which ephrin and Eph exist respectively in a glial element and a neuronal element, is of theoretical importance. Moreover, our results also raise a possibility that suppression of ephrinB/EphB forward signaling may be a new strategy for ameliorating RGC apoptosis in glaucoma.
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影响因子：
6.2
作者：
Eastlake K;Banerjee PJ;Angbohang A;Charteris DG;Khaw PT;Limb GA
通讯作者：
Limb GA
影响因子：
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作者：
Harada, Takayuki;Harada, Chikako;Tanaka, Kohichi
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Tanaka, Kohichi
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Brambilla, Roberta;Ashbaugh, Jessica Jopek;Bethea, John R.
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Bethea, John R.
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Greenberg, ME
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作者：
Du, Juan;Tran, Tony;Sretavan, David W.
通讯作者：
Sretavan, David W.