Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. Recent work in animal models suggests that a critical neuroinflammatory event damages retinal ganglion cell axons in the optic nerve head during ocular hypertensive injury. We previously demonstrated that monocyte-like cells enter the optic nerve head in an ocular hypertensive mouse model of glaucoma (DBA/2 J), but their roles, if any, in mediating axon damage remain unclear. To understand the function of these infiltrating monocyte-like cells, we used RNA-sequencing to profile their transcriptomes. Based on their pro-inflammatory molecular signatures, we hypothesized and confirmed that monocyte-platelet interactions occur in glaucomatous tissue. Furthermore, to test monocyte function we used two approaches to inhibit their entry into the optic nerve head: (1) treatment with DS-SILY, a peptidoglycan that acts as a barrier to platelet adhesion to the vessel wall and to monocytes, and (2) genetic targeting of Itgam (CD11b, an immune cell receptor that enables immune cell extravasation). Monocyte specific RNA-sequencing identified novel neuroinflammatory pathways early in glaucoma pathogenesis. Targeting these processes pharmacologically (DS-SILY) or genetically (Itgam / CD11b knockout) reduced monocyte entry and provided neuroprotection in DBA/2 J eyes. These data demonstrate a key role of monocyte-like cell extravasation in glaucoma and demonstrate that modulating neuroinflammatory processes can significantly lessen optic nerve injury.

中文翻译：

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抑制单核细胞样细胞外渗可预防DBA / 2J青光眼的神经退行性变

青光眼的特征在于进行性功能障碍和视网膜神经节细胞丧失。在动物模型中的最新工作表明，在眼部高压性损伤期间，严重的神经炎症事件会损害视神经头部的视网膜神经节细胞轴突。我们以前曾证明过，在青光眼的高眼压小鼠模型（DBA / 2 J）中，单核细胞样细胞会进入视神经头部，但是它们在介导轴突损伤中的作用（如果有的话）仍然不清楚。为了了解这些浸润的单核细胞样细胞的功能，我们使用了RNA测序技术来分析其转录组。基于它们的促炎分子特征，我们假设并确认了青光眼组织中发生了单核细胞-血小板相互作用。此外，为了测试单核细胞功能，我们使用了两种方法来抑制单核细胞进入视神经头：（1）使用DS-SILY（一种肽聚糖，可作为血小板粘附到血管壁和单核细胞的屏障）进行处理，以及（2）Itgam的遗传靶向（CD11b，一种能够使免疫细胞外渗的免疫细胞受体）。单核细胞特异的RNA测序在青光眼发病机理的早期确定了新的神经炎性途径。药理学（DS-SILY）或遗传学（Itgam / CD11b敲除）靶向这些过程可减少单核细胞进入并为DBA / 2 J眼睛提供神经保护。这些数据证明了单核细胞样细胞外渗在青光眼中的关键作用，并证明调节神经炎症过程可以显着减轻视神经损伤。使免疫细胞外渗的免疫细胞受体）。单核细胞特异的RNA测序在青光眼发病机理的早期确定了新的神经炎性途径。药理学（DS-SILY）或遗传学（Itgam / CD11b敲除）靶向这些过程可减少单核细胞进入并在DBA / 2 J眼睛中提供神经保护作用。这些数据证明了单核细胞样细胞外渗在青光眼中的关键作用，并证明调节神经炎症过程可以显着减轻视神经损伤。使免疫细胞外渗的免疫细胞受体）。单核细胞特异的RNA测序在青光眼发病机理的早期确定了新的神经炎性途径。药理学（DS-SILY）或遗传学（Itgam / CD11b敲除）靶向这些过程可减少单核细胞进入并为DBA / 2 J眼睛提供神经保护。这些数据证明了单核细胞样细胞外渗在青光眼中的关键作用，并证明调节神经炎症过程可以显着减轻视神经损伤。