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Corneal lymphangiogenesis facilitates ocular surface inflammation and cell trafficking in dry eye disease

 Yong Woo Ji  ;  Jae Lim Lee  ;  Hyun Goo Kang  ;  Nayeong Gu  ;  Haewon Byun  ;  Areum Yeo  ;  Hyemi Noh  ;  Soyoung Kim  ;  Eun Young Choi  ;  Jong Suk Song  ;  Hyung Keun Lee 
 OCULAR SURFACE, Vol.16(3) : 306-313, 2018 
Journal Title
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Dry eye ; LYVE-1 ; Lymphangiogenesis ; Lymphatic vessel ; VEGFR2
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-1Cre;VEGFR2flox 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-1Cre;VEGFR2flox 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-α, IL-6/-8/-12/-17, VEGF-C/-D, IFN-γ, 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-1Cre;VEGFR2flox mice. After DE induction, mRNA levels of TNF-α, IL-8, and IFN-γ were significantly reduced in Lyve-1Cre;VEGFR2flox mice compared to WT mice (p < .01). Surprisingly, the LNs from Lyve-1Cre;VEGFR2flox 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-1Cre;VEGFR2flox mice were notably intact like in the naïve 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.
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1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kang, Hyun Goo(강현구) ORCID logo https://orcid.org/0000-0001-8359-9618
Kim, So Young(김소영)
Noh, Hae Mi(노혜미)
Yeo, Areum(여아름)
Lee, Hyung Keun(이형근) ORCID logo https://orcid.org/0000-0002-1123-2136
Ji, Yong Woo(지용우)
Choi, Eun Young(최은영) ORCID logo https://orcid.org/0000-0002-1668-6452
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