title: IL-17 and VEGF are necessary for efficient corneal nerve regeneration.
abstract: 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(+) γδ T cells, neutrophils, and platelets in the cornea followed by full restoration of the epithelium and ∼19% regeneration of sensory nerves within 96 hours. Mice deficient in γδ T cells (TCRδ(-/-)) 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-GP1bα 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 γδ T cell-dependent inflammatory cascade involving IL-17, neutrophils, platelets, and VEGF-A in corneal nerve regeneration.
authors.affiliation: Section of Leukocyte Biology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Li
authors.forename: Alan R
authors.initials: AR
authors.lastname: Burns
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.forename: Rolando E
authors.initials: RE
authors.lastname: Rumbaut
authors.forename: C Wayne
authors.initials: CW
authors.lastname: Smith
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D003315:Cornea / Q000294:innervation* / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D009416:Nerve Regeneration; D009504:Neutrophils / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D019007:P-Selectin; D016692:Receptors, Antigen, T-Cell, gamma-delta; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1