Ferroptosis involves in intestinal epithelial cell death in ulcerative colitis
Ferroptosis involves in intestinal epithelial cell death in ulcerative colitis
复制标题
铁死亡参与溃疡性结肠炎的肠上皮细胞死亡
DOI：
10.1038/s41419-020-2299-1
复制
发表时间：
2020-02-03
影响因子：
9
通讯作者：
Wu, Bin
中科院分区：
文献类型：
--
作者：
Xu, Minyi;Tao, Jin;Wu, Bin
铁死亡最近作为一种铁依赖性非凋亡细胞死亡形式出现，这也是一种受调节的坏死过程和对肿瘤抑制的反应。然而，铁死亡是否与溃疡性结肠炎（UC）有关尚不清楚。本研究的目的是探讨铁死亡是否与UC，特别是肠上皮细胞（IEC）死亡有关，并分析核因子κBp65亚基（NF-κBp65）对铁死亡的影响。在人类 UC 肠粘膜样本中评估了铁死亡相关蛋白的基因表达。采用葡聚糖硫酸钠(DSS)诱导UC实验模型。评估IECs的铁死亡，并使用IEC特异性NF-κBp65缺失小鼠（p65IEC-KO）分析NF-κBp65对铁死亡的影响，并在体外和体内研究铁死亡信号通路。结果表明，UC患者和结肠炎小鼠的IECs显着诱导铁死亡，并且铁死亡是由内质网（ER）应激信号介导的。 IECNF-κBp65的特异性缺失明显上调铁死亡并加剧结肠炎，结果表明磷酸化的NF-κBp65通过直接结合真核起始因子2α显着抑制ER应激信号传导。这些数据表明，铁死亡通过内质网应激介导的 IEC 细胞死亡促进 UC，并且 NF-κBp65 磷酸化抑制内质网应激介导的 IEC 铁死亡，从而缓解 UC。结果表明，铁死亡参与了UC的IEC死亡，NF-κBp65在铁死亡抑制中发挥着关键作用，铁死亡是UC的潜在治疗靶点。
Ferroptosis has recently emerged as an iron-dependent form of nonapoptotic cell death, which is also a regulated necrosis process and a response to tumor suppression. However, whether ferroptosis is involved in ulcerative colitis (UC) is unknown. The aims of this study were to investigate whether the ferroptosis is involved in UC, particularly intestinal epithelial cell (IEC) death, and to analyze the effect of the nuclear factor kappa Bp65 subunit (NF-κBp65) on ferroptosis. The gene expression of ferroptosis-related proteins was assessed in intestinal mucosal samples from human UC. The experimental model of UC was induced with dextran sulfate sodium (DSS). Ferroptosis of IECs was evaluated, the effect of NF-κBp65 on ferroptosis was analyzed by using IEC-specificNF-κBp65-deleted mice (p65IEC-KO), and the ferroptosis signaling pathway was investigated in vitro and in vivo. The results showed that ferroptosis was significantly induced in the IECs from UC patients and mice with colitis, and the ferroptosis was mediated by endoplasmic reticulum (ER) stress signaling. The specific deletion of IECNF-κBp65clearly upregulated ferroptosis and exacerbated colitis, and the result showed that phosphorylated-NF-κBp65 significantly inhibited ER stress signaling by directly binding eukaryotic initiation factor 2α. These data indicate that ferroptosis contributes to UC via ER stress-mediated IEC cell death, and that NF-κBp65 phosphorylation suppresses ER stress-mediated IEC ferroptosis to alleviate UC. The results suggest that ferroptosis involves in IEC death in UC, NF-κBp65 play a critical role in the ferroptotic inhibition, and ferroptosis is a potential therapeutic target for UC.