Proteotranscriptomic analyses reveal distinct interferon-beta signaling pathways and therapeutic targets in choroidal neovascularization

Aim: To investigate the molecular mechanism underlying the onset of choroidal neovascularization (CNV). Methods: Integrated transcriptomic and proteomic analyses of retinas in mice with laser-induced CNV were performed using RNA sequencing and tandem mass tag. In addition, the laser-treated mice received systemic interferon-beta (IFN-beta) therapy. Measurements of CNV lesions were acquired by the confocal analysis of stained choroidal flat mounts. The proportions of T helper 17 (Th17) cells were determined by flow cytometric analysis. Results: A total of differentially expressed 186 genes (120 up-regulated and 66 down-regulated) and 104 proteins (73 up-regulated and 31 down-regulated) were identified. The gene ontology and KEGG pathway analyses indicated that CNV was mainly associated with immune and inflammatory responses, such as cellular response to IFN-beta and Th17 cell differentiation. Moreover, the key nodes of the protein-protein interaction network mainly involved up-regulated proteins, including alpha A crystallin and fibroblast growth factor 2, and were verified by Western blotting. To confirm the changes in gene expression, real-time quantitative PCR was performed. Furthermore, levels of IFN-beta in both the retina and plasma, as measured by enzyme-linked immunosorbent assay (ELISA), were significantly lower in the CNV group than in the control group. IFN-beta treatment significantly reduced CNV lesion size and promoted the proliferation of Th17 cells in laser-treated mice. Conclusions: This study demonstrates that the occurrence of CNV might be associated with the dysfunction of immune and inflammatory processes and that IFN-beta could serve as a potential therapeutic target.