Corneal lymphangiogenesis facilitates ocular surface inflammation and cell trafficking in dry eye disease
- Authors
- Ji, Yong Woo; Lee, Jae Lim; Kang, Hyun Goo; Gu, Nayeong; Byun, Haewon; Yeo, Areum; Noh, Hyemi; Kim, Soyoung; Choi, Eun Young; Song, Jong Suk; Lee, Hyung Keun
- Issue Date
- 7월-2018
- Publisher
- ELSEVIER SCIENCE BV
- Keywords
- Lymphatic vessel; Lymphangiogenesis; Dry eye; LYVE-1; VEGFR2
- Citation
- OCULAR SURFACE, v.16, no.3, pp.306 - 313
- Indexed
- SCIE
SCOPUS
- Journal Title
- OCULAR SURFACE
- Volume
- 16
- Number
- 3
- Start Page
- 306
- End Page
- 313
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/74471
- DOI
- 10.1016/j.jtos.2018.03.008
- ISSN
- 1542-0124
- Abstract
- Purpose: While the normal cornea has limited innervation by the lymphatic system, chronic immune-inflammatory disorders such as dry eye (DE) can induce lymphangiogenesis in the ocular surface. Using a conditional knock-down murine model, Lyve-1(Cre);VEGFR2(flox) mice, this study investigated the role of lymphangiogenesis in the pathophysiology of DE. Methods: DE was induced in both wild type (WT) B6 and Lyve-1(Cre);VEGFR2(flox) mice. Tissue immunostaining and volumetric gross measurements were used to assess changes in the ocular surface, skin, and lymph nodes (LNs). The expression of lymphangiogenic factors (TNF-alpha, IL-6/-8/-12/-17, VEGF-C/-D, IFN-gamma, VEGFR-2/-3, Lyve-1, and podoplanin) and the frequency of immune cells (CD4, CD11b, and CD207) on the ocular surface and lacrimal glands were quantified by real-time polymerase chain reaction and flow cytometry. Results: Compared to WT mice, there were fewer lymphatic vessels and a reduction in lymphangiogenic markers in the ocular surface and skin of Lyve-1(Cre);VEGFR2(flox) mice. After DE induction, mRNA levels of TNF-alpha, IL-8, and IFN-gamma were significantly reduced in Lyve-1(Cre);VEGFR2(flox) mice compared to WT mice (p < .01). Surprisingly, the LNs from Lyve-1(Cre);VEGFR2(flox) mice with DE were significantly smaller and populated by fewer dendritic cells and effector T cells than those from WT mice (p < .001). Furthermore, immunostaining showed corneal nerves in the DE-induced Lyve-1(Cre);VEGFR2(flox) mice were notably intact like in the naive condition. Conclusions: Inhibition of lymphangiogenesis in the cornea effectively attenuates not only the inflammatory response including trafficking of immune cells but also preserves corneal nerves under desiccating stress. Corneal lymphangiogenesis might be a contributing factor in deterioration on the ocular surface homeostasis. (C) 2018 Elsevier Inc. All rights reserved.
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