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HIF1α-mediated TRAIL Expression Regulates Lacrimal Gland Inflammation in Dry Eye Disease

Authors
 Yong Woo Ji  ;  Joon H Lee  ;  Eun Young Choi  ;  Hyun Goo Kang  ;  Kyoung Yul Seo  ;  Jong Suk Song  ;  Hyeon Chang Kim  ;  Hyung Keun Lee 
Citation
 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, Vol.61(1) : 3, 2020-01 
Journal Title
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
ISSN
 0146-0404 
Issue Date
2020-01
MeSH
Animals ; Apoptosis ; Coculture Techniques ; Dacryocystitis / metabolism* ; Dacryocystitis / pathology ; Disease Models, Animal ; Dry Eye Syndromes / metabolism* ; Dry Eye Syndromes / pathology ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Gene Expression Regulation / physiology* ; Hypoxia-Inducible Factor 1, alpha Subunit / physiology* ; Immunoblotting ; In Situ Nick-End Labeling ; Lacrimal Apparatus / metabolism* ; Lacrimal Apparatus / pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Organ Culture Techniques ; Real-Time Polymerase Chain Reaction ; TNF-Related Apoptosis-Inducing Ligand / genetics*
Abstract
Purpose: The purpose of this study was to investigate the expression of death ligands in the lacrimal glands (LGs), identify upstream factors that regulate their expression, and determine the functional roles of these factors in the pathogenesis of dry eye disease (DED).

Methods: For DED experiment, ex vivo coculture system with LG and in vivo murine model using a controlled environment chamber were utilized. C57BL/6 mice and hypoxia-inducible factor (HIF)-1α conditional knockout (CKO) mice were used. Immunohistochemical staining, polymerase chain reaction, and immunoblotting were performed to determine levels of death ligands including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in DED-induced LGs. Additionally, acinar cell and CD45+ cell apoptosis was determined with neutralizing TRAIL treatment.

Results: Desiccating stress significantly increased HIF-1α expression in LG-acinar cells. Furthermore, HIF-1α deficiency significantly enhanced the infiltration of CD45+ inflammatory cells in LG and induced LG-acinar cell death. Meanwhile, only TRAIL expression was increased in DED-LG, but abrogated in HIF-1α CKO. Interestingly, the main source of TRAIL was the CD45- LG-acinar cells, but not CD45+ immune cells after DED induction. Using ex vivo coculture system, we confirmed LG-induced apoptosis of immune cells via HIF-1α-mediated TRAIL secretion following DED. Consistent with ex vivo, the insufficiency of HIF-1α and TRAIL enhanced recruitment of inflammatory cells to the LG and subsequently exacerbated ocular surface damage in DED mice.

Conclusions: Our findings offer novel insight into the regulatory function of acinar cell-derived TRAIL in limiting inflammatory damage and could be implicated in the development of potential therapeutic strategies for DED.
Files in This Item:
T202002610.pdf Download
DOI
10.1167/iovs.61.1.3
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Preventive Medicine (예방의학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hyun Goo(강현구) ORCID logo https://orcid.org/0000-0001-8359-9618
Kim, Hyeon Chang(김현창) ORCID logo https://orcid.org/0000-0001-7867-1240
Seo, Kyoung Yul(서경률) ORCID logo https://orcid.org/0000-0002-9855-1980
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
Choi, Eun Young(최은영) ORCID logo https://orcid.org/0000-0002-1668-6452
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/178966
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