Havener Eye Institute, Department of Ophthalmology and Visual Science, The Ohio State University Wexner Medical Center, Columbus, OH, 43212, USA.
Division Human Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, 43240, USA.
Sci Rep. 2017 Oct 30;7(1):14336. doi: 10.1038/s41598-017-14298-9.
Photoreceptor death and retinal gliosis underlie the majority of vision threatening retinal diseases including retinal detachment (RD). Although the underlying pathobiology of vision limiting processes in RD is not fully understood, inflammation is known to play a critical role. We conducted an iTRAQ proteomic screen of up- and down-regulated proteins in a murine model of RD to identify potential targetable candidates. Macrophage migration inhibitory factor (MIF) was identified and evaluated for neurotoxic and pro-gliotic effects during RD. Systemic administration of the MIF inhibitor ISO-1 significantly blocked photoreceptor apoptosis, outer nuclear layer (ONL) thinning, and retinal gliosis. ISO-1 and MIF knockout (MIFKO) had greater accumulation of Müller glia pERK expression in the detached retina, suggesting that Müller survival pathways might underlie the neuroprotective response. Our data show the feasibility of the MIF-inhibitor ISO-1 to block pathological damage responses in retinal detachment and provide a rationale to explore MIF inhibition as a potential therapeutic option for RD.
光感受器细胞死亡和视网膜神经胶质增生是大多数威胁视力的视网膜疾病（包括视网膜脱离）的基础。尽管视网膜脱离中限制视力的过程的潜在病理生物学尚未完全阐明，但已知炎症起着关键作用。我们对视网膜脱离的小鼠模型中上调和下调的蛋白质进行了 iTRAQ 蛋白质组学筛选，以鉴定潜在的可靶向候选物。鉴定出巨噬细胞移动抑制因子（MIF），并评估其在视网膜脱离过程中的神经毒性和促神经胶质增生作用。MIF 抑制剂 ISO-1 的系统给药显著阻断了光感受器细胞凋亡、外核层（ONL）变薄和视网膜神经胶质增生。ISO-1 和 MIF 基因敲除（MIFKO）在脱离的视网膜中有更多的 Müller 胶质 pERK 表达的积累，这表明 Müller 细胞存活途径可能是神经保护反应的基础。我们的数据表明 MIF 抑制剂 ISO-1 阻断视网膜脱离中病理性损伤反应的可行性，并为探索 MIF 抑制作为治疗视网膜脱离的潜在治疗选择提供了依据。
