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

Abstract

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 hypoxiainducible 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 apoptosisinducing 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 cellderived TRAIL in limiting inflammatory damage and could be implicated in the development of potential therapeutic strategies for DED.

Aprepitant Restores Corneal Sensitivity and Reduces Pain in DED

“…Indeed, the literature suggests that DED is associated with the infiltration of activated leukocytes in the lacrimal glands, and that this mechanistically induces lachrymal gland disfunction. 63 – 66 Our data also corroborate our previous finding that NK1R was upregulated in the lacrimal gland of graft-versus-host disease mice, and that NK1R antagonist administration improved tear secretion. 59 …”

The Dopaminergic Neuronal System Regulates the Inflammatory Status of Mouse Lacrimal Glands in Dry Eye Disease

“…T- and B-cell levels were significantly increased in LGs after DE induction, as we reported previously. 23 – 25 Surprisingly, dopaminergic receptor blockade significantly increased the percentage of infiltrating cells. Furthermore, all levels of three cell types that were investigated (CD3 + , CD4 + , and CD19 + ) were significantly increased only via the inhibition of DR2 and not that of DR1 ( Fig.…”

Corneal Lymphangiogenesis: Current Pathophysiological Understandings and Its Functional Role in Ocular Surface Disease

“…We believe that our study and that by Dana and Goyal complements one another, and together, they provide strong evidence that corneal lymphangiogenesis facilitates immune cell activation, enhances pro-inflammatory cytokines, damages corneal nerves, and aggravates clinical scores [ 91 ]. Although lymphangiogenesis in the ocular surface is critical under DED conditions, LV growth proved more prominent in the lacrimal gland in the desiccated murine model from our previous studies [ 74 , 93 ] and communications with others (Chauhan, Sunil). Moreover, comparing ocular surfaces, protein biomarkers, and immune cell infiltrations were more abundant in the lacrimal gland than in the ocular surface and tears [ 94 ].…”