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Activation of Dll4/Notch Signaling and Hypoxia-Inducible Factor-1 Alpha Facilitates Lymphangiogenesis in Lacrimal Glands in Dry Eye

 Ji Hwan Min  ;  Chul Hee Lee  ;  Yong Woo Ji  ;  Areum Yeo  ;  Hyemi Noh  ;  Insil Song  ;  Eung Kweon Kim  ;  Hyung Keun Lee 
 PLOS ONE, Vol.11(2) : e0147846, 2016 
Journal Title
Issue Date
Animals ; Down-Regulation ; Dry Eye Syndromes/metabolism* ; Dry Eye Syndromes/pathology ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Intracellular Signaling Peptides and Proteins/metabolism* ; Lacrimal Apparatus/metabolism* ; Lacrimal Apparatus/pathology ; Leukocyte Common Antigens/metabolism ; Lymphangiogenesis* ; Male ; Membrane Proteins/metabolism* ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Biological ; Receptors, Notch/metabolism* ; Signal Transduction* ; Up-Regulation
PURPOSE: By using hypoxia-inducible factor-1 alpha conditional knockout (HIF-1α CKO) mice and a dry eye (DE) mouse model, we aimed to determine the role played by delta-like ligand 4 (Dll4)/Notch signaling and HIF-1α in the lymphangiogenesis of lacrimal glands (LGs). METHODS: C57BL/6 mice were housed in a controlled-environment chamber for DE induction. During DE induction, the expression level of Dll4/Notch signaling and lymphangiogenesis in LGs was measured by quantitative RT-PCR, immunoblot, and immunofluorescence staining. Next, lymphangiogenesis was measured after Dll4/Notch signal inhibition by anti-Dll4 antibody or γ-secretase inhibitor. Using HIF-1α CKO mice, the expression of Dll4/Notch signaling and lymphangiogenesis in LGs of DE-induced HIF-1α CKO mice were assessed. Additionally, the infiltration of CD45+ cells in LGs was assessed by immunohistochemical (IHC) staining and flow cytometry for each condition. RESULTS: DE significantly upregulated Dll4/Notch and lymphangiogenesis in LGs. Inhibition of Dll4/Notch significantly suppressed lymphangiogenesis in LGs. Compared to wild-type (WT) mice, DE induced HIF-1α CKO mice showed markedly low levels of Dll4/Notch and lymphangiogenesis. Inhibition of lymphangiogenesis by Dll4/Notch suppression resulted in increased CD45+ cell infiltration in LGs. Likewise, CD45+ cells infiltrated more in the LGs of HIF-1α CKO DE mice than in non-DE HIF-1α CKO mice. CONCLUSIONS: Dll4/Notch signaling and HIF-1α are closely related to lymphangiogenesis in DE-induced LGs. Lymphangiogenesis stimulated by Dll4/Notch and HIF-1α may play a role in protecting LGs from DE-induced inflammation by aiding the clearance of immune cells from LGs.
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1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Orthopedic Surgery (정형외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Eung Kweon(김응권) ORCID logo https://orcid.org/0000-0002-1453-8042
Min, Ji Hwan(민지환)
Lee, Chul Hee(이철희)
Lee, Hyung Keun(이형근) ORCID logo https://orcid.org/0000-0002-1123-2136
Ji, Yong Woo(지용우) ORCID logo https://orcid.org/0000-0002-7211-6278
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