Key Laboratory of Yunnan Province, Yunnan Eye Institute, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, Yunnan, China.
Department of Pathology and Pathophysiology, Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, China.
Cell Death Dis. 2024 Feb 8;15(2):118. doi: 10.1038/s41419-024-06499-8.
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.
糖尿病性视网膜病变是糖尿病常见的微血管并发症，也是失明的主要原因。细胞焦亡已成为参与糖尿病性视网膜病变发病机制的一种细胞死亡机制。本研究探讨了 GSDME 介导的细胞焦亡及其在糖尿病性视网膜病变中的调节作用。我们发现 GSDME 在糖尿病性视网膜病变的进展中上调。高葡萄糖促进视网膜内皮细胞和视网膜色素上皮细胞中 GSDME 诱导的细胞焦亡，归因于 caspase-3 的激活，caspase-3 将 GSDME 切割生成执行细胞焦亡的 N 端片段。TNFSF15 被鉴定为 GSDME 介导的细胞焦亡的结合伴侣和抑制剂。高葡萄糖增加 TNFSF15 的表达，但 caspase-3 激活剂 Raptinal 抑制其表达。此外，TNFSF15 蛋白通过与视网膜细胞中的 GSDME 相互作用抑制高葡萄糖和 Raptinal 诱导的细胞焦亡。总之，我们的研究结果表明，TNFSF15 通过阻断视网膜细胞中 GSDME 依赖性细胞焦亡来抑制糖尿病性视网膜病变的进展，提示 TNFSF15-GSDME 相互作用可能成为糖尿病性视网膜病变的有前途的治疗靶点。
