|Li, Zhijie -|
|Burns, Alan -|
|Han, Lei -|
|Rumbaut, Rolando -|
|Smith, Wayne -|
Submitted to: American Journal of Pathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 1, 2010
Publication Date: March 3, 2011
Citation: Li, Z., Burns, A.R., Han, L., Rumbaut, R.E., Smith, W.C. 2011. IL-17 and VEGF are necessary for efficient corneal nerve regeneration. American Journal of Pathology. 178(3):1106-16. Interpretive Summary: Inflammation plays a very important role in the body’s ability to resist infections, heal injured tissue and respond to cancer. We are interested in the influence of nutrition on inflammation and we study very basic mechanisms of inflammation. In this paper we analyze the proteins released by white blood cells as they arrive at a site of tissue injury that are necessary for the earliest healing of the tissue. We show that these white blood cells produce a protein called VEGF that directly stimulates the growth of injured nerves. The importance of this finding is that it is very important to maintain normal inflammation as a part of healing.
Technical 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(+) yo 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 yo T cells (TCRo(-/-)) 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-GP1ba 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 yo T cell-dependent inflammatory cascade involving IL-17, neutrophils, platelets, and VEGF-A in corneal nerve regeneration.