HIF1 alpha-mediated TRAIL Expression Regulates Lacrimal Gland Inflammation in Dry Eye Disease
- Authors
- Ji, Yong Woo; Lee, Joon H.; Choi, Eun Young; Kang, Hyun Goo; Seo, Kyoung Yul; Song, Jong Suk; Kim, Hyeon Chang; Lee, Hyung Keun
- Issue Date
- 1월-2020
- Publisher
- ASSOC RESEARCH VISION OPHTHALMOLOGY INC
- Keywords
- death ligand; tumor necrosis factor-related apoptosis-inducing ligand; hypoxia-inducible factor-1 alpha; lacrimal gland; dry eye disease
- Citation
- INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, v.61, no.1
- Indexed
- SCIE
SCOPUS
- Journal Title
- INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
- Volume
- 61
- Number
- 1
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/58553
- DOI
- 10.1167/iovs.61.1.3
- ISSN
- 0146-0404
- 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)-1 alpha 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-1 alpha expression in LG-acinar cells. Furthermore, HIF-1 alpha 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-1 alpha 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-1 alpha-mediated TRAIL secretion following DED. Consistent with ex vivo, the insufficiency of HIF-1 alpha 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.
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