The role of neprilysin in ocular surface homeostasis and corneal wound healing

Abstract Tear fluid is known to contain many different hormones with relevance for ocular surface homeostasis. We studied the presence and functional role of insulin-like factor 3 (INSL3) and its cognate receptor RXFP2 (relaxin/insulin-like family peptide receptor 2) at the ocular surface and in tears. Expression of human INSL3 and RXFP2 was determined in tissues of the ocular surface and lacrimal apparatus; in human corneal (HCE), conjunctival (HCjE), and sebaceous (SC) epithelial cell lines; and in human tears by RT-PCR and ELISA. We investigated effects of human recombinant INSL3 (hrINSL3) on cell proliferation and cell migration and the influence of hrINSL3 on the expression of MMP2, -9, and -13 and TIMP1 and -2 was quantified by real-time PCR and ELISA in HCE, HCjE, and SC cells. We used a C57BL/6 mouse corneal defect model to elucidate the effect of topical application of hrINSL3 on corneal wound healing. INSL3 and RXFP2 transcripts and INSL3 protein were detected in all tissues and cell lines investigated. Significantly higher concentrations of INSL3 were detected in tears from male vs. female volunteers. Stimulation of HCE, HCjE, and SC with hrINSL3 significantly increased cell proliferation in HCjE and SC and migration of HCjE. Treatment with hrINSL3 for 24 hours regulated MMP2, TIMP1, and TIMP2 expression. The local application of hrINSL3 onto denuded corneal surface resulted in significantly accelerated corneal wound healing in mice. These findings suggest a novel and gender-specific role for INSL3 and cognate receptor RXFP2 signaling in ocular surface homeostasis and determined a novel role for hrINSL3 in corneal wound healing.

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The Role of Extracellular Matrix in Corneal Wound Healing

Cornea ◽

10.1097/ico.0b013e3182a4786b ◽

2013 ◽

Vol 32 ◽

pp. S43-S45 ◽

Cited By ~ 8

Author(s):

Osamu Yamanaka ◽

Takayoshi Sumioka ◽

Shizuya Saika

Keyword(s):

Extracellular Matrix ◽

Wound Healing ◽

Corneal Wound Healing ◽

Corneal Wound

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Role of VIP and Sonic Hedgehog signaling pathways in mediating epithelial wound healing, sensory nerve regeneration and their defects in diabetic corneas

10.2337/figshare.12168084 ◽

2020 ◽

Author(s):

Ada Admin ◽

Yangyang Zhang ◽

Nan Gao ◽

Lin Wu ◽

Patrick S. Y. Lee ◽

...

Keyword(s):

Wound Healing ◽

Nerve Regeneration ◽

Sonic Hedgehog ◽

Sensory Nerve ◽

Dependent Manner ◽

Corneal Wound Healing ◽

Epithelial Wound Healing ◽

Corneal Wound ◽

Diabetic Keratopathy

Diabetic Keratopathy, a sight-threatening corneal disease, comprises several symptomatic conditions including delayed epithelial wound healing, recurrent erosions, and sensory nerve (SN) neuropathy. We investigated the role of neuropeptides in mediating corneal wound healing, including epithelial wound closure and SN regeneration. Denervation by Resiniferatoxin severely impaired corneal wound healing and markedly up-regulated pro-inflammatory gene expression. Exogenous neuropeptides CGRP, SP, and VIP partially reversed Resiniferatoxin’s effects, with VIP specifically inducing IL-10 expression. Hence, we focused on VIP and observed that wounding induced VIP and VIPR1 expression in normal (NL), but not diabetic (DM) mouse corneas. Targeting VIPR1 in <em>NL</em> corneas attenuated corneal wound healing, dampened wound-induced expression of neurotrophic factors, and exacerbated inflammatory responses while exogenous VIP had the opposite effects in DM corneas. Remarkably, wounding and diabetes also affected the expression of Sonic Hedgehog (SHH) in a VIP-dependent manner. Downregulating SHH expression in NL corneas decreased, while exogenous SHH in DM corneas increased the rates of corneal wound healing. Furthermore, inhibition of SHH signaling dampened VIP-promoted corneal wound healing. We conclude that VIP regulates epithelial wound he<a></a><a>aling, inflammatory response, and nerve regeneration in the corneas in a</a> SHH-dependent manner, suggesting a therapeutic potential for these molecules in treating diabetic keratopathy.

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