Background:There is growing evidence that the TIR-domain-containing adapter-inducing interferon-β (TRIF) pathway is implicated in the modulation of neuroinflammation following injuries to the brain and retina. After exposure to injury or to excitotoxic pathogens, toll-like receptors (TLR) activatethe innate immune system signaling cascade and stimulate the release of inflammatory cytokines. Inhibition of the TLR4 receptor has been shown to enhance retinal ganglion cell (RGC) survival in optic nerve crush (ONC) and in ischemic injury to other parts of the brain. Objective:Based on this evidence, we tested the hypothesis that mice with the TRIF gene knocked out (TKO) will demonstrate decreased inflammatory responses and greater functional recovery after ONC. Methods:Four experimental groups –TKO ONC (12 males and 8 females), WT ONC (10 males and 8 females), TKO sham (9 males and 5 females), and WT sham (7 males and 5 females) –were used as subjects. Visual evoked potentials (VEP) were recorded in the left and right primary visual cortices and optomotor response were assessed in all mice at 14, 30, and 80 days after ONC. GFAP and Iba-1 were used as markers for astrocytes and microglial cells respectively at 7 days after ONC, along with NF-kB to measure inflammatory effects downstream of TRIF activation; RMPBS marker was used to visualize RGC survival and GAP-43 was used as a marker of regenerating optic nerve axons at 30 days after ONC. Results:We found reduced inflammatory response in the retina at 7 days post-ONC, less RGC loss and greater axonal regeneration 30 days post-ONC, and better recovery of visual function 80 days post-ONC in TKO mice compared to WT mice. Conclusions:Our study showed that the TRIF pathway is involved in post-ONC inflammatory response and gliosis and that deletion of TRIF induces better RGC survival and regeneration and better functional recovery in mice. Our results suggest the TRIF pathway as a potential therapeutic target for reducing the inflammatory damage caused by nervous system injury.

中文翻译：

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雄性和雌性野生型和 TRIF 缺陷小鼠视神经挤压后的视力恢复

背景：越来越多的证据表明，包含 TIR 结构域的接头诱导干扰素-β (TRIF) 通路与大脑和视网膜损伤后神经炎症的调节有关。暴露于损伤或兴奋毒性病原体后，toll​​ 样受体 (TLR) 激活先天免疫系统信号级联并刺激炎症细胞因子的释放。已显示抑制 TLR4 受体可提高视神经挤压 (ONC) 和大脑其他部位缺血性损伤中视网膜神经节细胞 (RGC) 的存活率。目的：基于这一证据，我们检验了这样一个假设，即 TRIF 基因敲除 (TKO) 的小鼠在 ONC 后会表现出炎症反应减少和功能恢复更大的假设。方法：四个实验组——TKO ONC（12男8女），WT ONC（10男8女）、TKO假手术（9男5女）和WT假手术（7男5女）被用作受试者。在 ONC 后 14、30 和 80 天，在左右初级视觉皮层中记录视觉诱发电位 (VEP)，并评估所有小鼠的视运动反应。在 ONC 后 7 天，GFAP 和 Iba-1 分别用作星形胶质细胞和小胶质细胞的标志物，与 NF-kB 一起用于测量 TRIF 激活下游的炎症效应；RMPBS 标记用于可视化 RGC 存活率，GAP-43 用作 ONC 后 30 天再生视神经轴突的标记。结果：我们发现，与 WT 小鼠相比，TKO 小鼠在 ONC 后 7 天视网膜中的炎症反应减少，在 ONC 后 30 天，RGC 损失更少，轴突再生更多，在 ONC 后 80 天，视觉功能恢复更好。结论：我们的研究表明 TRIF 通路参与 ONC 后炎症反应和神经胶质增生，TRIF 的缺失可诱导小鼠更好的 RGC 存活和再生以及更好的功能恢复。我们的研究结果表明，TRIF 通路是减少神经系统损伤引起的炎症损伤的潜在治疗靶点。