Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic Conditions
Tear hyperosmolarity plays an essential role in the initiation and progression of dry-eye disease. Under a hyperosmotic environment, corneal epithelial cells experience perturbations in endoplasmic reticulum function that can lead to proinflammatory signaling and apoptosis. In this study, we investi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/9/4528 |
| _version_ | 1797504743284670464 |
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| author | Damien Guindolet Ashley M. Woodward Eric E. Gabison Pablo Argüeso |
| author_facet | Damien Guindolet Ashley M. Woodward Eric E. Gabison Pablo Argüeso |
| author_sort | Damien Guindolet |
| collection | DOAJ |
| description | Tear hyperosmolarity plays an essential role in the initiation and progression of dry-eye disease. Under a hyperosmotic environment, corneal epithelial cells experience perturbations in endoplasmic reticulum function that can lead to proinflammatory signaling and apoptosis. In this study, we investigated the effect of tauroursodeoxycholic acid (TUDCA), a chemical chaperone known to protect against endoplasmic reticulum stress, on corneal epithelial cells exposed to hyperosmotic conditions. We found that the expression of the genes involved in the activation of the unfolded protein response and the pro-apoptotic transcription factor <i>DDIT3</i> were markedly upregulated in patients with Sjögren’s dry-eye disease and in a human model of corneal epithelial differentiation following treatment with hyperosmotic saline. Experiments in vitro demonstrated that TUDCA prevented hyperosmotically induced cell death by reducing nuclear DNA fragmentation and caspase-3 activation. TUDCA supplementation also led to the transcriptional repression of <i>CXCL8</i> and <i>IL5</i>, two inflammatory mediators associated with dry-eye pathogenesis. These studies highlight the role of hyperosmotic conditions in promoting endoplasmic reticulum stress in the cornea and identify TUDCA as a potential therapeutic agent for the treatment of dry-eye disease. |
| first_indexed | 2024-03-10T04:08:41Z |
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| id | doaj.art-ec23798c6efb40ccbeb18f92f2d283a5 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:08:41Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ec23798c6efb40ccbeb18f92f2d283a52023-11-23T08:18:30ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01239452810.3390/ijms23094528Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic ConditionsDamien Guindolet0Ashley M. Woodward1Eric E. Gabison2Pablo Argüeso3Schepens Eye Research Institute of Mass. Eye and Ear, Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, MA 02114, USASchepens Eye Research Institute of Mass. Eye and Ear, Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, MA 02114, USAHôpital Fondation A. de Rothschild, 25 rue Manin, 75019 Paris, FranceSchepens Eye Research Institute of Mass. Eye and Ear, Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, MA 02114, USATear hyperosmolarity plays an essential role in the initiation and progression of dry-eye disease. Under a hyperosmotic environment, corneal epithelial cells experience perturbations in endoplasmic reticulum function that can lead to proinflammatory signaling and apoptosis. In this study, we investigated the effect of tauroursodeoxycholic acid (TUDCA), a chemical chaperone known to protect against endoplasmic reticulum stress, on corneal epithelial cells exposed to hyperosmotic conditions. We found that the expression of the genes involved in the activation of the unfolded protein response and the pro-apoptotic transcription factor <i>DDIT3</i> were markedly upregulated in patients with Sjögren’s dry-eye disease and in a human model of corneal epithelial differentiation following treatment with hyperosmotic saline. Experiments in vitro demonstrated that TUDCA prevented hyperosmotically induced cell death by reducing nuclear DNA fragmentation and caspase-3 activation. TUDCA supplementation also led to the transcriptional repression of <i>CXCL8</i> and <i>IL5</i>, two inflammatory mediators associated with dry-eye pathogenesis. These studies highlight the role of hyperosmotic conditions in promoting endoplasmic reticulum stress in the cornea and identify TUDCA as a potential therapeutic agent for the treatment of dry-eye disease.https://www.mdpi.com/1422-0067/23/9/4528corneal epitheliumdry eyeendoplasmic reticulum stresshyperosmotic stresstauroursodeoxycholic acidunfolded protein response |
| spellingShingle | Damien Guindolet Ashley M. Woodward Eric E. Gabison Pablo Argüeso Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic Conditions International Journal of Molecular Sciences corneal epithelium dry eye endoplasmic reticulum stress hyperosmotic stress tauroursodeoxycholic acid unfolded protein response |
| title | Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic Conditions |
| title_full | Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic Conditions |
| title_fullStr | Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic Conditions |
| title_full_unstemmed | Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic Conditions |
| title_short | Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic Conditions |
| title_sort | alleviation of endoplasmic reticulum stress enhances human corneal epithelial cell viability under hyperosmotic conditions |
| topic | corneal epithelium dry eye endoplasmic reticulum stress hyperosmotic stress tauroursodeoxycholic acid unfolded protein response |
| url | https://www.mdpi.com/1422-0067/23/9/4528 |
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