Corneal lymphangiogenesis ameliorates corneal inflammation and edema in late stage of bacterial keratitis

Akitomo Narimatsu,Tetsuya Matsumoto,Takaaki Hattori,Kazuki Tajima,Hiroshi Goto,Yoshihiko Usui,Naohito Koike,Naoyuki Yamakawa,Hayate Nakagawa,Shigeto Kumakura

doi:10.1038/s41598-019-39876-x

Abstract

Lymphatic vessels play a crucial role in systemic immune response and regulation of tissue fluid homeostasis. Corneal lymphangiogenesis in bacterial keratitis has not been studied. In this study, we investigated the mechanism and the role of corneal lymphangiogenesis in a murine bacterial keratitis model using Pseudomonas aeruginosa. We first demonstrated that corneal lymphangiogenesis was enhanced mainly in the late stage of bacterial keratitis, contrary to corneal angiogenesis that started earlier. Corresponding to the delayed lymphangiogenesis, expression of the pro-lymphangiogenic factors VEGF-C and VEGFR-3 increased in the late stage of bacterial keratitis. We further found that F4/80 and CD11b positive macrophages played an essential role in corneal lymphangiogenesis. Notably, macrophages were specifically involved in corneal lymphangiogenesis in the late stage of bacterial keratitis. Finally, we demonstrated the beneficial role of corneal lymphangiogenesis in ameliorating the clinical course of bacterial keratitis. Our study showed that bacterial activity was not directly involved in the late stage of keratitis, while corneal lymphangiogenesis reduced corneal edema and clinical manifestation in the late stage of bacterial keratitis. These findings suggest that the process of lymphangiogenesis in bacterial keratitis ameliorates corneal inflammation and edema in the late stage of bacterial keratitis.

Highlights

The lymphatic vascular system plays an important role in tissue fluid homeostasis and systemic immune response[1]
The percentage of lymphatic vessels increased significantly in the infected group on day 14 post-inoculation, there was no significant difference between the infected and control groups on day 7 post-inoculation. These data indicated that lymphangiogenesis was involved in bacterial keratitis, and that corneal lymphangiogenesis was mainly enhanced in the late stage of bacterial keratitis as compared to earlier increase of corneal angiogenesis
We revealed the distinctive mechanism of corneal lymphangiogenesis in a murine bacterial keratitis model using Pseudomonas aeruginosa, which is the common bacterial species causing contact lens-related bacterial keratitis[25,26]

Summary

Introduction

The lymphatic vascular system plays an important role in tissue fluid homeostasis and systemic immune response[1]. The mechanism by which how lymph vessel spouts into inflamed corneas was well investigated using various models such as suture placement[4,13,14], alkali burn[15], thermal injury[16], herpetic keratitis[17,18], dry eye[19], cornea transplantation[20,21] allergic disease[22] and acute corneal edema[23] Based on these studies, corneal lymphangiogenesis is mainly promoted by VEGF-C through VEGFR-3 signaling. Recent studies have reported that lymphangiogenesis plays a beneficial role in the regulation of corneal edema in acute corneal edema, suggesting that lymphatic vessels may contribute to reduce immune cells and edema[23,33]. The role of lymphangiogenesis during bacterial keratitis has not been studied

Methods

Results

Conclusion