Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.
Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States.
Front Immunol. 2020 Nov 13;11:585918. doi: 10.3389/fimmu.2020.585918. eCollection 2020.
Retinal ischemia/reperfusion injury (RI) is a common cause of irreversible visual impairment and blindness in elderly and critical unmet medical need. While no effective treatment is available for RI, microglial activation and local immune responses in the retina are thought to play important roles in the pathophysiology of neurodegeneration. While survival and activation of microglia depend critically on colony-stimulating factor receptor (CSF-1R) signaling, it remains unclear if targeting the retinal immune microenvironments by CSF-1RAb after RI is sufficient to rescue vision and present a potentially effective therapy. Here we used rodent models of RI and showed that retinal ischemia induced by acute elevation of intraocular pressure triggered an early activation of microglia and macrophages in the retina within 12 h. This was followed by lymphocyte infiltration and increased production of pro-inflammatory cytokines. Intravitreal injection of CSF-1R neutralizing antibody (CSF-1RAb) after RI significantly blocked microglial activation and the subsequent T cell recruitment. This also led to improved retinal ganglion cell survival and function measured by cell quantification and electroretinogram positive scotopic threshold responses, as well as increased visual acuity and contrast sensitivity as assessed by optomotor reflex-based assays, when compared to the isotype-treated control group. Moreover, the administration of CSF-1RAb efficiently attenuated inflammatory responses and activation of human microglia in culture, suggesting a therapeutic target with human relevance. These results, together with the existing clinical safety profiles, support that CSF-1RAb may present a promising therapeutic avenue for RI, a currently untreatable condition, by targeting microglia and the immune microenvironment in the retina to facilitate neural survival and visual function recovery.
视网膜缺血/再灌注损伤（RI）是老年人视力不可逆损害和失明的常见原因，也是目前尚未满足的重大医疗需求。尽管目前尚无有效的 RI 治疗方法，但认为小胶质细胞激活和视网膜局部免疫反应在神经退行性变的病理生理学中发挥重要作用。虽然小胶质细胞的存活和激活依赖于集落刺激因子受体（CSF-1R）信号，但尚不清楚 RI 后通过 CSF-1RAb 靶向视网膜免疫微环境是否足以挽救视力并提供一种潜在有效的治疗方法。在这里，我们使用了 RI 的啮齿动物模型，并表明急性升高眼内压引起的视网膜缺血在 12 小时内引发了视网膜中小胶质细胞和巨噬细胞的早期激活。随后是淋巴细胞浸润和促炎细胞因子的产生。RI 后玻璃体内注射 CSF-1R 中和抗体（CSF-1RAb）可显著阻断小胶质细胞激活和随后的 T 细胞募集。与同种型处理对照组相比，这也导致视网膜神经节细胞存活和功能的改善，通过细胞定量和视网膜电图暗适应阈值反应测量，以及视力和对比敏感度的提高，通过基于光感受器反射的测定评估。此外，CSF-1RAb 的给药有效地减弱了培养中的人类小胶质细胞的炎症反应和激活，表明该药物具有人类相关性的治疗靶点。这些结果，加上现有的临床安全性概况，支持 CSF-1RAb 通过靶向视网膜中的小胶质细胞和免疫微环境来促进神经存活和视觉功能恢复，从而为目前无法治疗的 RI 提供一种有前途的治疗途径。
