IL-17 and VEGF Are Necessary for Efficient Corneal Nerve Regeneration

The contribution of acute inflammation to sensory nerve regeneration was investigated in the murine cornea using a model of corneal abrasion that removes the stratified epithelium and subbasal nerve plexus. Abrasion induced accumulation of IL-17(+) CCR6(+) gamma delta T cells, neutrophils, and platelets in the cornea followed by full restoration of the epithelium and similar to 19% regeneration of sensory nerves within 96 hours. Mice deficient in gamma delta T cells (TCR delta(-/-)) or wild-type mice treated systemically with anti-IL-17 had > 50% reduction in leukocyte and platelet infiltration and > 50% reduction in nerve regeneration. Strategies used to prevent neutrophil and platelet accumulation (eg, wild-type mice treated with anti-Ly6G or anti-GP1b alpha antibody to deplete neutrophils or platelets) also resulted in > 50% reductions in corneal nerve density. Infiltrating neutrophils and platelets stained positively for VEGF-A, tissue levels of VEGF-A peaked coincidentally with peak tissue levels of neutrophils and platelets, depletion of neutrophils before injury reduced tissue VEGF-A levels by > 70%, and wild-type mice treated systemically with anti-VEGF-A antibody exhibited > 80% reduction in corneal nerve regeneration. Given the known trophic effects of VEGF-A for neurite growth, the results in this report demonstrate a previously unrecognized beneficial role for the gamma delta T cell-dependent inflammatory cascade involving IL-17, neutrophils, platelets, and VEGF-A in corneal nerve regeneration. (Am J Pathol 2011, 178:1106-1116; DOI: 10.1016/j.ajpath.2010.12.001)