Transcriptomics of Various Diseases Reveals the Core Role of Immune System Pathways in Retinal Damage Repair and Nerve Regeneration

Abstract

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.

Keywords: Glaucoma; Immune; Mice; Optic nerve; Optic nerve crush; Optic neuritis; Retina.