Abstract
Netrins are secreted chemoattractants with the roles in axon guidance, cell migration and epithelial plasticity. In the present study, we investigated the roles of netrin-1 in the regulation of corneal epithelial wound healing, inflammation response and nerve fiber regeneration in diabetic mice and cultured corneal epithelial cells. In diabetic mice, the expression of netrin-1 was decreased when compared with that of normal mice. Furthermore, high glucose blocked the wounding-induced up-regulation of netrin-1 expression in corneal epithelial cells. Exogenous netrin-1 promoted the corneal epithelial wound healing in diabetic mice, and facilitated the proliferation and migration by reactivating the phosphorylation of ERK and EGFR in high-glucose treated corneal epithelial cells. Moreover, netrin-1 decreased the neutrophil infiltration and promoted M2 macrophage transition, accompanied with the attenuated expression of pro-inflammatory factors in diabetic mouse corneal epithelium. The promotions of netrin-1 on corneal epithelial wound healing and inflammation resolution were mediated at least through the adenosine 2B receptor. In addition, netrin-1 promoted the regeneration of corneal nerve fibers that was impaired in diabetic mice. Taken together, netrin-1 regulates corneal epithelial wound healing, inflammation response and nerve fiber regeneration in diabetic mice, indicating the potential application for the therapy of diabetic keratopathy.
Highlights
The corneal epithelium is subjected continuously to physical, chemical, and biological insults, often resulting in a wound and loss of barrier functions
The immunofluorescence staining of netrin-1 in normal and diabetic unwound mice corneal sections showed that the expression of netrin-1 in diabetic mouse was decreased (Fig. 1A)
To elucidate the mechanism underlying the promotion of netrin-1 on corneal epithelial wound healing, we investigated the effects of netrin-1 on the upregulation of EGF expression and activation of ERK and EGFR that were impaired in diabetic corneal epithelium
Summary
The corneal epithelium is subjected continuously to physical, chemical, and biological insults, often resulting in a wound and loss of barrier functions. Neurotrophic deficits may play a major role in the pathogenesis of diabetic keratopathy, the most recognized diabetic complication in cornea, as the corneal nerve fibers are reported to exert important trophic influences and contribute to the maintenance of corneal epithelium homeostasis[7]. Based on the multiple functions of netrin-1 and the characteristics of diabetic corneal pathogenesis, we hypothesized that netrin-1 may assume a potential use for the treatment of diabetic keratopathy. To address this hypothesis, we studied the regulation and mechanism of netrin-1 on corneal epithelial wound healing, inflammatory response, and nerve fiber regeneration by using type 1 diabetic mice and high glucose-treated corneal epithelial cells
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