Progressive photoreceptor death occurs in blinding diseases such as retinitis pigmentosa. Myeloid differentiation primary response protein 88 (MyD88) is a central adaptor protein for innate immune system Toll-like receptors (TLR) and induces cytokine secretion during retinal disease. We recently demonstrated that inhibiting MyD88 in mouse models of retinal degeneration led to increased photoreceptor survival, which was associated with altered cytokines and increased neuroprotective microglia. However, the identity of additional molecular changes associated with MyD88 inhibitor-induced neuroprotection is not known. In this study, we used isobaric tags for relative and absolute quantification (iTRAQ) labelling followed by LC-MS/MS for quantitative proteomic analysis on the rd10 mouse model of retinal degeneration to identify protein pathways changed by MyD88 inhibition. Quantitative proteomics using iTRAQ LC-MS/MS is a high-throughput method ideal for providing insight into molecular pathways during disease and experimental treatments. Forty-two proteins were differentially expressed in retinas from mice treated with MyD88 inhibitor compared with control. Notably, increased expression of multiple crystallins and chaperones that respond to cellular stress and have anti-apoptotic properties was identified in the MyD88-inhibited mice. These data suggest that inhibiting MyD88 enhances chaperone-mediated retinal protection pathways. Therefore, this study provides insight into molecular events contributing to photoreceptor protection from modulating inflammation.

中文翻译：

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视网膜变性 10 小鼠神经保护性 MyD88 抑制后的定量蛋白质组学分析

进行性光感受器死亡发生在致盲疾病中，例如色素性视网膜炎。髓样分化初级反应蛋白 88 (MyD88) 是先天免疫系统 Toll 样受体 (TLR) 的中心衔接蛋白，可在视网膜疾病期间诱导细胞因子分泌。我们最近证明，在视网膜变性小鼠模型中抑制 MyD88 会导致光感受器存活率增加，这与细胞因子的改变和神经保护性小胶质细胞的增加有关。然而，与 MyD88 抑制剂诱导的神经保护相关的其他分子变化的特性尚不清楚。在本研究中，我们使用等压标签进行相对和绝对定量 (iTRAQ) 标记，然后使用 LC-MS/MS 对rd10进行定量蛋白质组学分析 视网膜变性的小鼠模型，以识别由 MyD88 抑制改变的蛋白质通路。使用 iTRAQ LC-MS/MS 进行定量蛋白质组学是一种高通量方法，非常适合深入了解疾病和实验治疗期间的分子途径。与对照组相比，用 MyD88 抑制剂治疗的小鼠的视网膜中有 42 种蛋白质存在差异表达。值得注意的是，在 MyD88 抑制的小鼠中发现了多种晶体蛋白和伴侣蛋白的表达增加，这些晶体蛋白和伴侣蛋白对细胞应激有反应并具有抗凋亡特性。这些数据表明，抑制 MyD88 可增强伴侣介导的视网膜保护途径。因此，这项研究提供了对有助于光感受器保护免受调节炎症的分子事件的深入了解。