Long Huirong, Xiong Yucong, Liu Haiyu, Yang Meiling, Liu Ting, Gong Chaoju, Li Suyan
Xuzhou Key Laboratory of Ophthalmology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Institute of Xuzhou, Xuzhou, 221100, China.
Department of Ophthalmology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Institute of Xuzhou, Xuzhou, 221100, China.
Inflammation. 2024 Nov 25. doi: 10.1007/s10753-024-02192-2.
Chronic inflammation has been associated with the progression of age-related macular degeneration (AMD) and diabetic retinopathy (DR), and the levels of various inflammatory factors are significantly increased in intraocular fluids of patients with AMD and DR. Therefore, elucidating the roles of inflammatory factors in the oxidative damage of RPE cells will help uncover the pathogenesis of AMD and DR. We have previously demonstrated that E2F1 plays an important role in the antioxidant capacity of RPE cells. Here, our transcriptome analysis shows that E2F1 affected the expressions of DNA repair genes in RPE cells. In addition, we found that E2F1 transactivated the splicing factor SRSF1. SRSF1 knockdown promoted DNA oxidative damage and apoptosis and decreased the mRNA stability of DNA repair genes XRCC2, POLK and LIG4 in RPE cells. Moreover, we found that SRSF1 could bind to the RNA stabilizing factor MATR3, and knockdown of the latter affected the mRNA stability of these DNA repair genes. Notably, interleukin-6 (IL-6), an inflammatory factor upregulated in intraocular fluids of patients with AMD and DR, decreased SRSF1 expression by inducing acetylation of E2F1 at the K125 position. Consistently, SRSF1 overexpression relieved IL-6-induced DNA oxidative damage and apoptosis in RPE cells. In vivo experiment results also confirmed that IL-6 could aggravate retinal oxidative damage. In conclusion, high levels of IL-6 in the eyes of patients with AMD and DR destabilize the mRNAs of DNA repair genes by disrupting the expression of SRSF1, leading to abnormal repair of DNA oxidative damage in RPE cells.
慢性炎症与年龄相关性黄斑变性（AMD）和糖尿病视网膜病变（DR）的进展相关，在AMD和DR患者的眼内液中，各种炎症因子的水平显著升高。因此，阐明炎症因子在视网膜色素上皮（RPE）细胞氧化损伤中的作用将有助于揭示AMD和DR的发病机制。我们之前已经证明E2F1在RPE细胞的抗氧化能力中起重要作用。在此，我们的转录组分析表明E2F1影响RPE细胞中DNA修复基因的表达。此外，我们发现E2F1反式激活剪接因子SRSF1。敲低SRSF1会促进DNA氧化损伤和细胞凋亡，并降低RPE细胞中DNA修复基因XRCC2、POLK和LIG4的mRNA稳定性。此外，我们发现SRSF1可以与RNA稳定因子MATR3结合，敲低后者会影响这些DNA修复基因的mRNA稳定性。值得注意的是，白细胞介素-6（IL-6）是一种在AMD和DR患者眼内液中上调的炎症因子，通过诱导E2F1在K125位点的乙酰化来降低SRSF1的表达。一致地，SRSF1过表达减轻了IL-6诱导的RPE细胞中的DNA氧化损伤和细胞凋亡。体内实验结果也证实IL-6可加重视网膜氧化损伤。总之，AMD和DR患者眼中的高水平IL-6通过破坏SRSF1的表达使DNA修复基因的mRNA不稳定，导致RPE细胞中DNA氧化损伤的异常修复。
