Key role for inflammation-related signaling in the pathogenesis of myopia based on evidence from proteomics analysis

Abstract

The mechanisms underlying myopia pathogenesis are not well understood. Using publicly-available human and animal datasets, we expound on the roles of known, implicated proteins, and new myopia-related signaling pathways were hypothesized. Proteins identified from human serum or ocular fluids, and from ocular tissues in myopic animal models, were uploaded and analyzed with the QIAGEN Ingenuity Pathway Analysis (IPA) software (March 2023). With each IPA database update, more potentially-relevant proteins and signaling pathways previously unavailable during data acquisition are added, allowing extraction of novel conclusions from existing data. Canonical pathway analysis was used to analyze these data and calculate an IPA activation z-score-which indicates not only whether an association is significant, but also whether the pathway is likely activated or inhibited. Cellular immune response and cytokine signaling were frequently found to be affected in both human and animal myopia studies. Analysis of two publicly-available proteomic datasets highlighted a potential role of the innate immune system and inflammation in myopia development, detailing specific signaling pathways involved such as Granzyme A (GzmA) and S100 family signaling in the retina, and activation of myofibroblast trans-differentiation in the sclera. This perspective in myopia research may facilitate development of more effective and targeted therapeutic agents.

Keywords: Inflammation; Innate immunity; Myopia; Proteomics; Signaling pathways.

Figure 1

Retinal signaling pathways in mice significantly affected by (A) imposed negative defocus (LIM vs control), and (B) the same, combined with application of atropine eye drops for 4 weeks after minus-lens induction for 2 weeks (atropine-treated LIM vs LIM), with (C) the respective z-scores of each newly identified signaling pathway in both groups. The x-axis represents statistical significance, and the y-axis represents pathway categories. Each bubble represents a signaling pathway, and the numbers inside the bubbles indicate the same signaling pathways in A and B. The colors of the bubbles indicate their relative effects on the signaling pathways that were significantly affected by the experimental treatment—from low activation (pink) to high activation (orange); from low inhibition (light blue) to high inhibition (dark blue); and no net activity (gray).

Figure 2

Signaling pathways significantly affected in the sclera of tree shrew: (A) after 11 days of imposed minus-defocus (LIM vs contralateral eyes), and (B) after 4 days of recovery from minus-lens treatment (treated eyes vs contralateral eyes), with (C) the respective z-score of each newly identified signaling pathway of both groups. The x-axis represents statistical significance, and the y-axis represents pathway categories. Each bubble represents a signaling pathway, and the numbers inside the bubbles indicate the same signaling pathways in (A) and (B). The colors of the bubbles indicate their relative effects on the signaling pathways that were significantly affected by the experimental treatment—from low activation (pink) to high activation (orange); from low inhibition (light blue) to high inhibition (dark blue); and no net activity (gray).