Role of toll-like receptor signaling in retinal ischemia

项目总结 缺血-再灌注(IR)损伤与视网膜的一系列病理情况有关，包括 青光眼、糖尿病视网膜病变、前部缺血性视神经病变和外伤性视神经病变。因此， 了解缺血性神经元损伤所涉及的事件可以为我们提供临床有效的治疗方法 治疗许多视网膜疾病。尽管这种损伤的原因是多因素的，但越来越多的实验证据表明 提示先天免疫系统在启动炎性级联反应中起着重要作用 视网膜功能的有害变化。Toll样受体(Toll-like Receptor，TLRs)是公认的 病原体引起的炎症的主要贡献者，最近是损伤引起的炎症。 从损伤/坏死细胞中释放的内源性配体可以激活TLRs，启动炎症反应 即使在没有病原体的情况下。我们已发表的结果表明，Toll的内源性配体水平- 类受体4(TLR4)增加视网膜IR，并通过激活TLR4参与视网膜损伤 以及由缺血损伤引发的炎症。重要的是，我们的初步结果表明 介导视网膜缺血性损伤的机制不仅是由于由 星形胶质细胞，小胶质细胞，或浸润性免疫细胞，但也通过激活视网膜神经节细胞(RGC)中的TLR4 他们自己。然而，TLR4信号诱导视网膜后炎症和损伤的确切机制 IR损伤情况尚不清楚。在这个项目中，我们假设TLR4信号在 视网膜IR损伤的发病机制直接和/或间接参与RGCs的损伤。这一假设 将在以下具体目标中概述的一系列实验中进行测试：1)确定TLR4 协调视网膜对IR损伤的免疫反应，以确定TLR4信号的沉默 减少缺血视网膜中的血视网膜通透性和白细胞的渗透，以确定 TLR4介导的信号直接损伤视网膜神经节细胞，以确定TLR4配体在缺血后视网膜中的作用。 完成这些具体目标可能会导致发现有助于防止损失的创新策略 视网膜缺血患者的视力，因为TLR4及其配体的选择性靶向可能是 对于开发预防IR损伤的治疗工具比针对细胞内损伤更有效 小路。

PROJECT SUMMARY Ischemia-reperfusion (IR) injury is implicated in a large array of pathological conditions in the retina including glaucoma, diabetic retinopathy, anterior ischemic optic neuropathy and traumatic optic neuropathy. Thus, understanding the events involved in ischemic neuronal injury can provide us with clinically effective treatments for many retinal diseases. Although the cause of this injury is multifactorial, increasing experimental evidence suggests an important role for the innate immune system in initiating the inflammatory cascade leading to detrimental/deleterious changes in retinal function. Toll-like receptors (TLRs) are recognized as one of the main contributors to pathogen-induced inflammation and, more recently, injury-induced inflammation. Endogenous ligands liberated from injured/necrotic cells can activate TLRs, initiating an inflammatory response even in the absence of pathogens. Our published results indicate that the level of endogenous ligands for toll- like receptor 4 (TLR4) increases in retinal IR and, through activation of TLR4, are involved in retinal damage and inflammation triggered by ischemic injury. Importantly, our preliminary results suggest that the mechanisms mediating ischemic damage in the retina are facilitated not only by inflammation induced by astrocytes, microglia, or infiltrating immune cells, but also by activation of TLR4 in retinal ganglion cells (RGCs) themselves. However, the exact mechanism of TLR4 signaling-induced inflammation and damage after retinal IR injury remains unknown. In this project we hypothesize that TLR4 signaling plays a significant role in the pathogenesis of retinal IR injury by directly and/or indirectly contributing to the injury of RGCs. This hypothesis will be tested in a series of experiments outlined in the following specific aims: 1) to determine whether TLR4 coordinates the immune response of the retina to IR injury~ 2) to determine whether silencing of TLR4 signaling reduces blood retinal permeability and infiltration of leukocytes in the ischemic retina~ 3) to determine whether TLR4-mediated signals directly injure RGCs~ 4) to define the role of TLR4 ligands in the post-ischemic retina. Completion of these specific aims could lead to the discovery of innovative strategies to help prevent the loss of vision in patients suffering from retinal ischemia, as selective targeting of both TLR4 and its ligands may be more effective for the development of therapeutic tools to prevent IR injury than targeting the intracellular pathways.