Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Erdao District, 126 Sendai Street, Changchun, Jilin Province 130033, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province 130062, China.
Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Erdao District, 126 Sendai Street, Changchun, Jilin Province 130033, China.
Int Immunopharmacol. 2024 Oct 25;140:112818. doi: 10.1016/j.intimp.2024.112818. Epub 2024 Jul 30.
Cell death caused by severe Staphylococcus aureus (S. aureus) infection is a fatal threat to humans and animals. However, whether ferroptosis, an iron-dependent form of cell death, is involved in S. aureus-induced cell death and its role in S. aureus-induced diseases are unclear. Using a mouse mastitis model and mammary epithelial cells (MMECs), we investigated the role of ferroptosis in the pathogenesis of S. aureus infection. The results revealed that S. aureus-induced ferroptosis in vivo and in vitro as demonstrated by dose-dependent increases in cell death; the level of malondialdehyde (MDA), the final product of lipid peroxidation; and dose-dependent decrease the production of the antioxidant glutathione (GSH). Treatment with typical inhibitors of ferroptosis, including ferrostatin-1 (Fer-1) and deferiprone (DFO), significantly inhibited S. aureus-induced death in MMECs. Mechanistically, treatment with S. aureus activated the protein kinase RNA-like ER kinase (PERK)-eukaryotic initiation factor 2, α subunit (eIF2α)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) pathway, which subsequently upregulated autophagy and promoted S. aureus-induced ferroptosis. The activation of autophagy degraded ferritin, resulting in iron dysregulation and ferroptosis. In addition, we found that excessive reactive oxygen species (ROS) production induced ferroptosis and activated endoplasmic reticulum (ER) stress, manifesting as elevated p-PERK-p-eIF2α-ATF4-CHOP pathway protein levels. Collectively, our findings indicate that ferroptosis is involved in S. aureus-induced mastitis via ER stress-mediated autophagy activation, implying a potential strategy for the prevention of S. aureus-associated diseases by targeting ferroptosis. In conclusion, the ROS-ER stress-autophagy axis is involved in regulating S. aureus-induced ferroptosis in MMECs. These findings not only provide a new potential mechanism for mastitis induced by S. aureus but also provide a basis for the treatment of other ferroptotic-related diseases.
金黄色葡萄球菌（S. aureus）感染引起的细胞死亡是人类和动物的致命威胁。然而，铁依赖性细胞死亡形式铁死亡是否参与 S. aureus 诱导的细胞死亡及其在 S. aureus 诱导的疾病中的作用尚不清楚。本研究使用小鼠乳腺炎模型和乳腺上皮细胞（MMECs），研究了铁死亡在 S. aureus 感染发病机制中的作用。结果表明，S. aureus 在体内和体外诱导铁死亡，表现为细胞死亡、脂质过氧化终产物丙二醛（MDA）水平以及抗氧化剂谷胱甘肽（GSH）产量呈剂量依赖性增加。典型的铁死亡抑制剂包括 Ferrostatine-1（Fer-1）和地拉罗司（DFO）处理显著抑制 MMECs 中 S. aureus 诱导的死亡。在机制上，S. aureus 处理激活蛋白激酶 RNA 样内质网激酶（PERK）-真核起始因子 2α 亚基（eIF2α）-激活转录因子 4（ATF4）-C/EBP 同源蛋白（CHOP）通路，随后上调自噬并促进 S. aureus 诱导的铁死亡。自噬降解铁蛋白，导致铁失调和铁死亡。此外，我们发现过量的活性氧（ROS）产生诱导铁死亡并激活内质网（ER）应激，表现为升高的 p-PERK-p-eIF2α-ATF4-CHOP 通路蛋白水平。综上所述，铁死亡通过 ER 应激介导的自噬激活参与 S. aureus 诱导的乳腺炎，表明通过靶向铁死亡治疗与 S. aureus 相关疾病具有潜在的策略。总之，ROS-ER 应激-自噬轴参与调节 MMECs 中 S. aureus 诱导的铁死亡。这些发现不仅为 S. aureus 诱导的乳腺炎提供了新的潜在机制，也为治疗其他铁死亡相关疾病提供了依据。
