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Zhijie Li, Debjani Gagen, Rolando Rumbaut, Alan R. Burns, Clifton W. Smith; IL-17 and VEGF are Necessary for Efficient Corneal Nerve Regeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2042.
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To explore the molecular mechanisms by which γΔ T cells promote corneal nerve regeneration after epithelial wounding.
A 2 mm diameter central epithelial region was mechanically debrided in male C57BL/6J (WT), TCRdelta-/-, and WT mice with platelet depletion by anti-CD42b, neutrophil depletion by anti-Ly6G, IL-17 blocking by anti-IL-17, or VEGF blocking by anti-VEGF. Corneas from each group were harvested at different times after wounding, and whole mounted corneas were analyzed by deconvolution microscopy for γΔ T cell phenotypes in the epithelium, platelet accumulation in the limbus, neutrophil accumulation near the injured subbasal nerve plexus, and subbasal nerve density across corneas.
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 wildtype mice treated with anti-IL-17 had >50% reduction in neutrophil and platelet infiltration and >50% reduction in nerve regeneration. Depletion of either neutrophils or platelets in wild-type mice also resulted in >50% reductions in corneal nerve density. Infiltrating neutrophils and platelets stained positively for VEGF-A, tissue levels of VEGF-A peaked coincident with peak tissue levels of neutrophils and platelets, depletion of neutrophils prior to injury reduced tissue VEGF-A levels by >70%, and wildtype mice treated with anti-VEGF-A antibody exhibited >80% reduction in corneal nerve regeneration.
The data presented here are consistent with the interpretation that CCR6+ IL-17+ γΔ T cells and IL-17 are necessary for early neutrophil and platelet-dependent delivery to the injured subbasal nerve plexus of VEGF-A, a trophic factor for neurite regeneration.
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