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TNFSF15 inhibits progression of diabetic retinopathy by blocking pyroptosis via interacting with GSDME
Hongkun Zhao1, Yating Dai2, Yunqin Li1
1Key Laboratory of Yunnan Province, Yunnan Eye Institute, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, Yunnan, China.
Abstract:
Diabetic retinopathy is a common microvascular complication of diabetes and a leading cause of blindness. Pyroptosis has emerged as a mechanism of cell death involved in diabetic retinopathy pathology. This study explored the role of GSDME-mediated pyroptosis and its regulation by TNFSF15 in diabetic retinopathy. We found GSDME was upregulated in the progression of diabetic retinopathy. High glucose promoted GSDME-induced pyroptosis in retinal endothelial cells and retinal pigment epithelial cells, attributed to the activation of caspase-3 which cleaves GSDME to generate the pyroptosis-executing N-terminal fragment. TNFSF15 was identified as a binding partner and inhibitor of GSDME-mediated pyroptosis. TNFSF15 expression was increased by high glucose but suppressed by the caspase-3 activator Raptinal. Moreover, TNFSF15 protein inhibited high glucose- and Raptinal-induced pyroptosis by interacting with GSDME in retinal cells. Collectively, our results demonstrate TNFSF15 inhibits diabetic retinopathy progression by blocking GSDME-dependent pyroptosis of retinal cells, suggesting the TNFSF15-GSDME interaction as a promising therapeutic target for diabetic retinopathy.
Insights
TNFSF15 inhibits diabetic retinopathy by blocking GSDME-mediated pyroptosis in retinal cells. This interaction presents a potential therapeutic target for preventing vision loss in diabetic patients.
Area of Science:
- Ophthalmology
- Cell Biology
- Endocrinology
Background:
- Diabetic retinopathy (DR) is a leading cause of blindness, driven by microvascular complications of diabetes.
- Pyroptosis, a pro-inflammatory cell death pathway, plays a significant role in DR pathogenesis.
Purpose of the Study:
- To investigate the role of Gasdermin E (GSDME)-mediated pyroptosis in DR.
- To explore the regulatory mechanism of TNFSF15 on GSDME-mediated pyroptosis in the context of DR.
Main Methods:
- Analyzing GSDME expression in DR progression.
- Investigating the effect of high glucose on pyroptosis in retinal cells.
- Identifying TNFSF15 as a GSDME binding partner and inhibitor.
- Assessing TNFSF15's effect on high glucose- and Raptinal-induced pyroptosis.
Main Results:
- GSDME was upregulated during DR progression.
- High glucose induced GSDME-mediated pyroptosis in retinal cells via caspase-3 activation.
- TNFSF15 expression increased with high glucose but was suppressed by Raptinal.
- TNFSF15 inhibited pyroptosis by interacting with GSDME in retinal cells.
Conclusions:
- TNFSF15 acts as an inhibitor of GSDME-dependent pyroptosis in retinal cells.
- The TNFSF15-GSDME interaction is a promising therapeutic target for inhibiting diabetic retinopathy progression.
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