Nerves, vessels and inflammation at the ocular surface

Abstract

AbstractCorneal nerves are essential in the maintenance of ocular surface homeostasis. The role of peripheral nerves in promoting the onset of corneal inflammation, instead, is only recently starting to emerge. The extremely dense sensory innervation, and complete absence of vessels, in the normal cornea, makes it an ideal target of neuroinflammation.Previous work from us demonstrated that acute nerve disruption is followed by corneal neovascularization and inflammation. We hypothesized that neuropeptide Substance P is a key modulator of corneal neuroinflammation. Indeed, our data show that neuropeptide Substance P is a key promoter of inflammation and neovascularization in pre‐clinical models of corneal burns, neovascularization, stem cell deficiency and ocular graft versus host disease. Further, we demonstrate that this effect is mediated by the Neurokinin 1 receptor, which is the principal receptor for Substance P. Moreover, we show that highly prevalent human corneal diseases/trauma are associated with increased Substance P expression in the tear fluid. This has significant clinical implication because medications are available to selectively block Neurokinin 1 receptor. Indeed, topical application of Neurokinin 1 receptor antagonists inhibits leukocyte infiltration, and ameliorate multiple clinical signs of inflammation in animal models of ocular surface inflammation.These data have allowed us to initiate a clinical trial for compassionate use of neurokinin 1 receptor antagonists for the treatment of recalcitrant ocular surface inflammation.