Myeloid differentiation protein 2 induced retinal ischemia reperfusion injury via upregulation of ROS through a TLR4-NOX4 pathway
Myeloid differentiation protein 2 induced retinal ischemia reperfusion injury via upregulation of ROS through a TLR4-NOX4 pathway
复制标题
骨髓分化蛋白2通过TLR4-NOX4途径上调ROS诱导视网膜缺血再灌注损伤
DOI：
10.1016/j.toxlet.2017.10.018
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发表时间：
2018-01-05
影响因子：
3.5
通讯作者：
Wang, Yi
中科院分区：
文献类型：
--
作者：
Chen, Huaicheng;Song, Zongming;Wang, Yi
视网膜缺血再灌注（I/R）损伤在许多眼科疾病中是常见的。最近的研究表明，Toll样受体4（TLR 4）参与缺血性视网膜损伤。TLR的激活需要特定的辅助蛋白，如髓样分化蛋白2（MD 2），其促进配体反应性。因此，抑制MD 2可能是调节TLR 4信号传导和缺血性视网膜损伤中有害下游效应的新方法。我们使用叔丁基过氧化氢（TBHP）处理的人Muller MIO-M1细胞建立体外I/R氧化损伤模型，并检测抑制MD 2的治疗效果。此外，我们在视网膜I/R损伤的小鼠模型中抑制了MD 2，并使用MD 2敲除小鼠证实了结果。我们的研究表明，MD 2的药理学抑制防止TBHP诱导的活性氧（ROS）的产生，炎症和随后的细胞凋亡的Muller细胞。我们还发现，视网膜I/R损伤诱导小鼠的功能缺陷，增加ROS水平，炎症和凋亡。在MD 2基因敲除小鼠中未观察到这些病理变化，并且当在野生型小鼠中抑制MD 2时，这些病理变化减弱。此外，我们发现这些治疗作用的机制涉及调节NADPH氧化酶4（NOX 4）-MD 2-TLR 4复合物的形成。本研究提供的证据表明，MD 2通过参与TLR 4-NOX 4复合物的形成以及氧化和炎症损伤的形成在视网膜I/R损伤的发病机制中起关键作用。因此，抑制MD 2可以减少视网膜I/R损伤期间TLR依赖性损伤。
Retinal ischemia reperfusion (I/R) injury is common in many ophthalmic diseases. Recent studies have shown that toll-like receptor 4 (TLR4) is involved in ischemic retinal injury. Activation of TLRs requires specific accessory proteins such as myeloid differentiation protein 2 (MD2), which facilitate in ligand responsiveness. Therefore, inhibiting MD2 may be a novel approach to modulate TLR4 signaling and deleterious downstream effects in ischemic retinal injury. We used human Muller MIO-M1 cells treated with tert-butyl hydroperoxide (TBHP) to establish an in vitro I/R model of oxidative injury and tested the therapeutic effect of inhibiting MD2. Furthermore, we inhibited MD2 in a mouse model of retinal I/R injury and confirmed the results using MD2 knockout mice. Our studies show that pharmacological inhibition of MD2 prevented TBHP-induced reactive oxygen species (ROS) generation, inflammation and subsequent apoptosis in Muller cells. We also show that retinal I/R injury in mice induced functional deficits, increased ROS levels, inflammation and apoptosis. These pathological changes were not observed in MD2 knockout mice and attenuated when MD2 was inhibited in wildtype mice. In addition, we discovered that the mechanism of these therapeutic effects involved regulation of NADPH oxidase 4 (NOX4)-MD2-TLR4 complex formation. This study provides evidence that MD2 plays a key role in the pathogenesis of retinal I/R damage by participating in TLR4-NOX4 complex formation and elaboration of oxidative and inflammatory damage. Hence, inhibition of MD2 may reduce TLR-dependent damage during retinal I/R injury.