Abstract
Calcitonin gene-related peptide (CGRP) is a multifunctional neuropeptide abundantly expressed by corneal nerves. Using a murine model of corneal mechanical injury, we found CGRP levels in the cornea to be significantly reduced after injury. Topical application of CGRP as an eye drop three times daily accelerates corneal epithelial wound closure, reduces corneal opacification, and prevents corneal edema after injury in vivo. We then used a series of in vitro and in vivo techniques to investigate the mechanisms underlying CGRP's functions. CGRP promotes corneal epithelial cell migration, proliferation, and the secretion of laminin. It reduces TGF-β1 signaling and prevents TGF-β1-mediated stromal fibroblast activation and tissue fibrosis. CGRP reduces corneal endothelial cell apoptosis and death, preserves cell density and morphology, and promotes their pump function, thus reducing edema. Lastly, CGRP reduces neutrophil infiltration, macrophage maturation, and the production of inflammatory cytokines in the cornea. Taken together, our results show that corneal nerve-derived CGRP plays a cyto-protective, pro-regenerative, anti-fibrotic, and anti-inflammatory role in corneal wound healing. Given that current treatment options for corneal injury and opacity are scarce, CGRP has significant therapeutic potential in this area of unmet medical needs. In addition, our results highlight the critical role of sensory nerves in ocular surface homeostasis and injury repair.