Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China.
Department of Anorectal Surgery, Xuzhou City Hospital of TCM, Xuzhou, China.
Biomol Biomed. 2023 May 1;23(3):437-449. doi: 10.17305/bjbms.2022.8081.
Ferroptosis is implicated in the progression of ulcerative colitis (UC), and interferon regulatory factor 7 (IRF7) contributes to cell death. This study probed the mechanism of IRF7 in ferroptosis of colonic epithelial cells (ECs) in mice with dextran sodium sulfate (DSS)-induced UC. The UC mouse model and the in vitro ferroptosis model were respectively established by DSS feeding and the treatment with FIN56 (a ferroptosis inducer). Results of quantitative real-time polymerase chain reaction and western blotting revealed the upregulation of IRF7 and solute carrier family 11 member 2 (SLC11A2/NRAMP2/DMT1) and the downregulation of microRNA (miR)-375-3p in DSS-treated mice and FIN56-treated ECs. Silencing of IRF7 improved the symptoms of UC in DSS-induced mice and decreased the levels of tumor necrosis factor α, interleukin 6, monocyte chemoattractant protein 1, and interleukin 1β, reactive oxygen species, iron ions, lipid peroxidation, and increased glutathione and glutathione peroxidase 4. Chromatin immunoprecipitation and dual-luciferase assays showed that binding of IRF7 to the miR-375-3p promoter inhibited miR-375-3p expression, and miR-375-3p suppressed SLC11A2 transcription. The rescue experiments revealed that knockdown of miR-375-3p neutralized the role of silencing IRF7 in alleviating ferroptosis of colonic ECs. Overall, IRF7 upregulated SLC11A2 transcription by inhibiting miR-375-3p expression, thereby prompting ferroptosis of colonic ECs and UC progression in DSS-treated mice.
铁死亡参与溃疡性结肠炎（UC）的进展，干扰素调节因子 7（IRF7）促进细胞死亡。本研究探讨了 IRF7 在葡聚糖硫酸钠（DSS）诱导的 UC 小鼠结肠上皮细胞（ECs）铁死亡中的作用机制。通过 DSS 喂养和 FIN56（铁死亡诱导剂）处理分别建立 UC 小鼠模型和体外铁死亡模型。实时定量聚合酶链反应和 Western blot 结果显示，DSS 处理的小鼠和 FIN56 处理的 ECs 中 IRF7 和溶质载体家族 11 成员 2（SLC11A2/NRAMP2/DMT1）上调，miR-375-3p 下调。IRF7 沉默改善了 DSS 诱导的 UC 小鼠的症状，降低了肿瘤坏死因子-α、白细胞介素 6、单核细胞趋化蛋白 1 和白细胞介素 1β、活性氧、铁离子、脂质过氧化和谷胱甘肽及谷胱甘肽过氧化物酶 4 的水平。染色质免疫沉淀和双荧光素酶报告基因检测显示，IRF7 与 miR-375-3p 启动子结合抑制 miR-375-3p 表达，miR-375-3p 抑制 SLC11A2 转录。挽救实验表明，miR-375-3p 敲低削弱了沉默 IRF7 缓解结肠 ECs 铁死亡的作用。总之，IRF7 通过抑制 miR-375-3p 的表达而上调 SLC11A2 转录，从而促进 DSS 处理的小鼠结肠 ECs 铁死亡和 UC 进展。
