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TNF-α released from retinal Müller cells aggravates retinal pigment epithelium cell apoptosis by upregulating
Yu Liu1, Lele Li2, Ningxin Pan1
1Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong, China.
Abstract:
Retinal pigment epithelium (RPE) cell damage, including mitophagy-associated cell apoptosis, accelerates the pathogenesis of diabetic retinopathy (DR), a common complication of diabetes that causes blindness. Müller cells interact with RPE cells via pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α). Herein, we investigated the role of the RPE cell epidermal growth factor receptor (EGFR)/p38 mitogen-activated protein kinase (p38)/nuclear factor kappa B (NF-κB) pathway in Müller cell-derived TNF-α-induced mitophagy-associated apoptosis during DR. Our results showed that TNF-α released from Müller cells activated the EGFR/p38/NF-κB/p62 pathway to increase mitophagy and apoptosis in RPE cells under high glucose (HG) conditions. Additionally, blockade of the TNF-α/EGFR axis alleviates blood-retina barrier breakdown in diabetic mice. Our data further illustrate the effects of the Müller cell inflammatory response on RPE cell survival, implying potential molecular targets for DR treatment.
Insights
Diabetic retinopathy (DR) involves retinal pigment epithelium (RPE) cell damage. Müller cells trigger RPE apoptosis via TNF-α, activating the EGFR/p38/NF-κB pathway, suggesting new DR treatment targets.
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Medicine
Background:
- Diabetic retinopathy (DR) is a leading cause of blindness, characterized by retinal pigment epithelium (RPE) cell damage and apoptosis.
- Mitophagy, a key cellular process, is implicated in RPE cell death during DR pathogenesis.
- Müller cells contribute to DR by releasing pro-inflammatory cytokines like tumor necrosis factor α (TNF-α), which affect RPE cells.
Purpose of the Study:
- To investigate the molecular mechanisms by which Müller cell-derived TNF-α induces mitophagy-associated apoptosis in RPE cells under high glucose conditions.
- To elucidate the role of the epidermal growth factor receptor (EGFR)/p38 mitogen-activated protein kinase (p38)/nuclear factor kappa B (NF-κB) signaling pathway in RPE cells during DR.
- To explore the therapeutic potential of targeting the TNF-α/EGFR axis for DR treatment.
Main Methods:
- Utilized cell culture models with high glucose exposure to mimic DR conditions.
- Investigated the activation of the EGFR/p38/NF-κB/p62 signaling pathway in RPE cells.
- Examined the effects of TNF-α on mitophagy and apoptosis in RPE cells.
- Assessed the impact of blocking the TNF-α/EGFR axis on the blood-retina barrier in a mouse model of diabetes.
Main Results:
- Tumor necrosis factor α (TNF-α) released from Müller cells activated the EGFR/p38/NF-κB/p62 pathway in RPE cells.
- This activation led to increased mitophagy and apoptosis in RPE cells under high glucose conditions.
- Blocking the TNF-α/EGFR interaction ameliorated blood-retina barrier disruption in diabetic mice.
Conclusions:
- Müller cell inflammation significantly impacts RPE cell survival in DR.
- The EGFR/p38/NF-κB pathway is a critical mediator of TNF-α-induced RPE cell death.
- Targeting the TNF-α/EGFR axis presents a promising therapeutic strategy for managing diabetic retinopathy.
