Ren Luqing, Tao Jianjian, Chen Huaicheng, Bian Yang, Yang Xi, Chen Gaozhi, Zhang Xin, Liang Guang, Wu Wencan, Song Zongming, Wang Yi
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Toxicol Appl Pharmacol. 2017 Feb 15;317:1-11. doi: 10.1016/j.taap.2017.01.001. Epub 2017 Jan 4.
Retinal ischemia-reperfusion (I/R) injury is a common pathological process in many eye disorders. Oxidative stress and inflammation play a role in retinal I/R injury. Recent studies show that toll-like receptor 4 (TLR4) is involved in initiating sterile inflammatory response in retinal I/R. However, the molecular mechanism by which TLR4 is activated is not known. In this study, we show that retinal I/R injury involves a co-receptor of TLR4, myeloid differentiation 2 (MD2). Inhibition of MD2 prevented cell death and preserved retinal function following retinal I/R injury. We confirmed these findings using MD2 knockout mice. Furthermore, we utilized human retinal pigment epithelial cells (ARPE-19 cells) to show that oxidative stress-induced cell death as well as inflammatory response are mediated through MD2. Inhibition of MD2 through a chemical inhibitor or knockdown prevented oxidative stress-induced cell death and expression of inflammatory cytokines. Oxidative stress was found to activate TLR4 in a MD2-dependent manner via increasing the expression of high mobility group box 1. In summary, our study shows that oxidative stress in retinal I/R injury can activate TLR4 signaling via MD2, resulting in induction of inflammatory genes and retinal damage. MD2 may represent an attractive therapeutic target for retinal I/R injury.
视网膜缺血再灌注（I/R）损伤是许多眼部疾病中常见的病理过程。氧化应激和炎症在视网膜I/R损伤中起作用。最近的研究表明，Toll样受体4（TLR4）参与启动视网膜I/R中的无菌性炎症反应。然而，TLR4被激活的分子机制尚不清楚。在本研究中，我们表明视网膜I/R损伤涉及TLR4的共受体髓样分化蛋白2（MD2）。抑制MD2可预防视网膜I/R损伤后的细胞死亡并保留视网膜功能。我们使用MD2基因敲除小鼠证实了这些发现。此外，我们利用人视网膜色素上皮细胞（ARPE-19细胞）表明氧化应激诱导的细胞死亡以及炎症反应是通过MD2介导的。通过化学抑制剂或基因敲低抑制MD2可预防氧化应激诱导的细胞死亡和炎症细胞因子的表达。发现氧化应激通过增加高迁移率族蛋白B1的表达以MD2依赖的方式激活TLR4。总之，我们的研究表明，视网膜I/R损伤中的氧化应激可通过MD2激活TLR4信号通路，导致炎症基因的诱导和视网膜损伤。MD2可能是视网膜I/R损伤的一个有吸引力的治疗靶点。
