Extraocular muscle-myokine-scleral remodeling axis: IL-6 trans-signaling as a novel mechanism in myopia development.

Abstract

PURPOSE: Myokines modulate biological processes in adjacent and distant tissues. Given the crucial role of extraocular muscles (EOMs) during prolonged near work, this study investigated whether contracting EOMs secrete IL-6 and other myokines to influence scleral remodeling in myopia, and identified downstream targets via bioinformatic analyses. METHODS: Tear IL-6 and soluble IL-6 receptor (sIL-6R) concentrations were measured before and after 2 h of near work. An electrical stimulation model was established to mimic sustained EOM contraction. To further assess the role of IL-6 trans-signaling, scleral fibroblasts were treated with conditioned medium (CM) containing the specific inhibitor olamkicept. In vivo, lens-induced myopia (LIM) guinea pigs were used to assess MMP-2 expression, and periocular injection of IL-6 overexpressing lentivirus was performed to examine axial length changes. Bioinformatics approaches were employed to evaluate the activation status of IL-6 trans-signaling. RESULTS: Tear IL-6 and sIL-6R levels increased significantly after prolonged near work. Electrically stimulated myotubes secreted more IL-6, and CM upregulated MMP-2 in scleral fibroblasts. However, this effect was significantly inhibited by the addition of olamkicept. In LIM guinea pigs, scleral MMP-2 were elevated, while IL-6 overexpression induced axial elongation. Bioinformatic analysis identified IL6R, IL1R1, ITGB3, and SERPINH1 as myopia-associated genes, and IL6ST, a core IL-6 receptor component, was upregulated in myopic tissues. CONCLUSION: This study establishes an "extraocular muscle-myokine-scleral remodeling" axis, providing experimental evidence for an endogenous inflammatory mechanism in myopia. It underscores IL-6 trans-signaling as a potential therapeutic target and offers new insights for myopia prevention and control.