Zhang Yuxiang, Pan Junjia, Zeng Deqin, Wang Yifan, Hu Chun, Chen Meilan
Guangdong Second Provincial General Hospital, Guangzhou, 510317, China.
Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, China.
Mol Neurobiol. 2025 Apr 17. doi: 10.1007/s12035-025-04929-y.
Retinal ganglion cells (RGCs) are the only neuronal bridges connecting retinal inputs to the brain's visual processing centers, enabling visual perception. The axon of RGCs forms the optic nerve, which transmits visual information to the visual cortex. Damage to RGCs and their axons results in irreversible visual impairment. Acute retinal damage is commonly induced by conditions such as optic nerve compression, glaucoma, and optic neuritis, for which effective clinical treatments are currently unavailable. Therefore, understanding the response of RGCs and their axons to injury is crucial for the development of potential treatments. This study utilizes multiple models including optic nerve crush (ONC), acute intraocular pressure (IOP) elevation, and local lipopolysaccharide (LPS) injection into the optic nerve to mimic eye diseases. Three days post-surgery, mice underwent retinal isolation followed by bulk-RNA sequencing to analyze differential gene expression among models. Using thresholds of |Log2 fold change (FC)|> 2 and p-value < 0.05, the significant gene expression changes observed in each model were as follows: ONC (upregulated, 456; downregulated, 84), IOP (upregulated, 1946; downregulated, 655), and LPS (upregulated, 219; downregulated, 94). Gene ontology (GO) analysis of the upregulated genes unexpectedly revealed that immune system pathways were the primary shared targets across all three models. In contrast, the downregulated genes exhibited model-specific enrichment: synaptic components and functions in IOP, neurogenesis and neuronal development in ONC, and inflammation and antioxidant in LPS. These findings were further confirmed by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. This suggests that managing immune activation is essential for treating acute retinal injury, and therapeutic strategies should address model-specific targets as well. Notably, 39 genes intersected across the models, and the protein-protein interaction (PPI) network identified Ccl5 as a key hub gene, underscoring its critical role in the pathophysiology of all three diseases.
视网膜神经节细胞（RGCs）是连接视网膜输入与大脑视觉处理中心的唯一神经元桥梁，使视觉感知成为可能。RGCs的轴突形成视神经，将视觉信息传递到视觉皮层。RGCs及其轴突受损会导致不可逆的视力损害。急性视网膜损伤通常由视神经压迫、青光眼和视神经炎等情况引起，目前尚无有效的临床治疗方法。因此，了解RGCs及其轴突对损伤的反应对于开发潜在治疗方法至关重要。本研究利用多种模型，包括视神经挤压（ONC）、急性眼压（IOP）升高和向视神经局部注射脂多糖（LPS）来模拟眼部疾病。手术后三天，对小鼠进行视网膜分离，然后进行批量RNA测序，以分析各模型之间的差异基因表达。使用|Log2倍数变化（FC）|> 2和p值< 0.05的阈值，在每个模型中观察到的显著基因表达变化如下：ONC（上调，456个；下调，84个），IOP（上调，1946个；下调，655个），以及LPS（上调，219个；下调，94个）。对上调基因的基因本体（GO）分析意外发现，免疫系统途径是所有三个模型的主要共同靶点。相比之下，下调基因表现出模型特异性富集：IOP中的突触成分和功能、ONC中的神经发生和神经元发育，以及LPS中的炎症和抗氧化。京都基因与基因组百科全书（KEGG）分析进一步证实了这些发现。这表明控制免疫激活对于治疗急性视网膜损伤至关重要，治疗策略也应针对模型特异性靶点。值得注意的是，39个基因在各模型中交叉，蛋白质-蛋白质相互作用（PPI）网络将Ccl5鉴定为关键枢纽基因，突出了其在所有三种疾病病理生理学中的关键作用。
