Th17/IL17 Mediates Autoimmunity-Dependent Corneal Lymphangiogenesis in Dry Eye Disease

Abstract

Purpose: : Th17 cells are the dominant pathogenic T effectors, causing damage to ocular surface epithelia in dry eye disease. Corneal lymphangiogenesis is a process induced in dry eye which contributes to disease progression. The purpose of this study was to investigate whether autoreactive Th17-secreted-IL17 contributes to corneal lymphangiogenesis in dry eye disease via stimulating the secretion of pro-lymphangiogenic factors by corneal epithelial cells.

Methods: : We first stimulated in vitro the primary human and murine corneal epithelial cells with IL17, and measured the expression levels of VEGF-A, -C and -D transcripts using real time PCR. Murine corneal pellet model was used to study the effects of IL17 pellet on lymphangiogenesis, and VEGF-D pellets were used as controls. Finally using a murine model of dry eye disease, we investigated the effects of in vivo topical blockade of IL17 on corneal lymphangiogenesis and the severity of disease.

Results: : IL17 significantly increased pro-lymphangiogenic VEGF-D secretion by both primary human and murine corneal epithelial cells in vitro. Growth of CD31^loLYVE1^hi lymphatic vessels in corneas with IL17 pellets was comparable to those in corneas with VEGF-D pellets. In vivo topical blockade of IL17 in dry eye corneas showed a significant reduction in corneal expression of VEGF-D and ingrowth of lymphatic vessels toward the central cornea which were paralleled with a significant decrease in the severity of the disease.

Conclusions: : Our data demonstrate that IL17 is a contributor to lymphangiogenesis in the dry eye cornea via induction of pro-lymphangiogenic VEGF-D. In addition, the findings that in vivo topical IL17 blockade leads to inhibition of lymphangiogenesis and diminished disease severity suggest a potential novel target for the treatment of dry eye disease.

Keywords: cornea: basic science • inflammation • vascular endothelial growth factor