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Updated: Jan 9, 2026
Induction of Ocular Surface Inflammation and Collection of Involved Tissues
Published on: August 4, 2022
Growth factor receptor-bound protein 2-mediated corneal epithelial injury drives depression-associated dry eye
Kuangqi Chen1, Ying Li2, Yinhao Wang3
1Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Eye Institute of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Jinan, Shandong, China; School of Ophthalmology, Shandong First Medical University, Jinan, Shandong, China; Shandong Eye Institute, Qingdao, China; Department of Ophthalmology, the First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang Province, China; Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
Abstract:
Depression is increasingly recognized as a comorbidity of dry eye disease (DED), yet its underlying mechanisms remain unclear. This study investigates the therapeutic effects of fluoxetine on depression-associated corneal injury and explores the molecular pathways involved. Chronic unpredictable mild stress (CUMS) mice received fluoxetine treatment. Behavioral tests, corneal wound healing, tear secretion, and 4D-DIA proteomics were performed. GRB2 expression was validated via immunohistochemistry, qRT-PCR, and western blot. Human corneal epithelial cells (hCECs) under hyperosmotic stress (450 mOsm) were transfected with GRB2 siRNA to assess oxidative stress, inflammation, and migration. Fluoxetine treatment significantly reduced depressive behaviors, accelerated corneal epithelial wound healing, and restored tear secretion. Proteomic analysis of corneal tissues revealed dysregulation of cytoskeletal and metabolic pathways in depressed mice, which fluoxetine partially reversed. GRB2 emerged as a critical protein, showing elevated expression in depressed mice and hyperosmolar-stressed hCECs. Silencing GRB2 in hCECs attenuated hyperosmolarity-induced oxidative stress, inflammation, and migration inhibition. Immunohistochemical and behavioral analyses confirmed GRB2's role in corneal epithelial thinning and depression-related DED pathology. These findings highlight GRB2 as a potential therapeutic target and underscore fluoxetine's dual efficacy in mitigating depressive symptoms and ocular surface damage. This study provides novel insights into the molecular interplay between depression and DED, advocating for integrated therapeutic strategies addressing both psychiatric and ophthalmic dimensions.
Insights
This study shows fluoxetine (an antidepressant) improves depression symptoms and heals corneal injury in mice. It identifies GRB2 protein as key in depression-related dry eye disease (DED), suggesting it as a therapeutic target.
Area of Science:
- Ophthalmology
- Neuroscience
- Molecular Biology
Background:
- Depression is a common comorbidity with dry eye disease (DED).
- The molecular mechanisms linking depression and DED are not well understood.
- Understanding these links is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the therapeutic effects of fluoxetine on depression-associated corneal injury.
- To explore the molecular pathways involved in depression and DED.
- To identify potential therapeutic targets for integrated treatment strategies.
Main Methods:
- Utilized a chronic unpredictable mild stress (CUMS) mouse model of depression.
- Administered fluoxetine and assessed behavioral, ocular, and proteomic changes.
- Investigated GRB2 protein expression and function in human corneal epithelial cells (hCECs) under stress.
Main Results:
- Fluoxetine reduced depressive behaviors, accelerated corneal healing, and restored tear secretion.
- Proteomics revealed fluoxetine partially reversed stress-induced pathway dysregulation.
- Elevated GRB2 expression was linked to depression-related DED; silencing GRB2 mitigated ocular stress responses.
Conclusions:
- Fluoxetine demonstrates dual efficacy in treating depression and DED.
- GRB2 is identified as a critical molecular player in depression-related DED.
- Targeting GRB2 offers a potential therapeutic strategy for combined psychiatric and ophthalmic conditions.
