Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China; Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Jining Medical University, Jining, China.
Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China.
Redox Biol. 2024 May;71:103100. doi: 10.1016/j.redox.2024.103100. Epub 2024 Mar 8.
Th2-high asthma is characterized by elevated levels of type 2 cytokines, such as interleukin 13 (IL-13), and its prevalence has been increasing worldwide. Ferroptosis, a recently discovered type of programmed cell death, is involved in the pathological process of Th2-high asthma; however, the underlying mechanisms remain incompletely understood. In this study, we demonstrated that the serum level of malondialdehyde (MDA), an index of lipid peroxidation, positively correlated with IL-13 level and negatively correlated with the predicted forced expiratory volume in 1 s (FEV1%) in asthmatics. Furthermore, we showed that IL-13 facilitates ferroptosis by upregulating of suppressor of cytokine signaling 1 (SOCS1) through analyzing immortalized airway epithelial cells, human airway organoids, and the ovalbumin (OVA)-challenged asthma model. We identified that signal transducer and activator of transcription 6 (STAT6) promotes the transcription of SOCS1 upon IL-13 stimulation. Moreover, SOCS1, an E3 ubiquitin ligase, was found to bind to solute carrier family 7 member 11 (SLC7A11) and catalyze its ubiquitinated degradation, thereby promoting ferroptosis in airway epithelial cells. Last, we found that inhibiting SOCS1 can decrease ferroptosis in airway epithelial cells and alleviate airway hyperresponsiveness (AHR) in OVA-challenged wide-type mice, while SOCS1 overexpression exacerbated the above in OVA-challenged IL-13-knockout mice. Our findings reveal that the IL-13/STAT6/SOCS1/SLC7A11 pathway is a novel molecular mechanism for ferroptosis in Th2-high asthma, confirming that targeting ferroptosis in airway epithelial cells is a potential therapeutic strategy for Th2-high asthma.
2 型高反应性哮喘的特征是 2 型细胞因子水平升高，如白细胞介素 13（IL-13），其患病率在全球范围内呈上升趋势。铁死亡是一种新发现的程序性细胞死亡方式，参与了 2 型高反应性哮喘的病理过程；然而，其潜在机制尚不完全清楚。在这项研究中，我们证明了丙二醛（MDA）水平，一种脂质过氧化的指标，与哮喘患者的 IL-13 水平呈正相关，与预测的 1 秒用力呼气量（FEV1%）呈负相关。此外，我们通过分析永生化的气道上皮细胞、人气道类器官和卵清蛋白（OVA）激发的哮喘模型，表明 IL-13 通过上调细胞因子信号转导抑制因子 1（SOCS1）促进铁死亡。我们发现信号转导和转录激活因子 6（STAT6）在受到 IL-13 刺激后促进 SOCS1 的转录。此外，SOCS1 作为一种 E3 泛素连接酶，被发现与溶质载体家族 7 成员 11（SLC7A11）结合并催化其泛素化降解，从而促进气道上皮细胞中的铁死亡。最后，我们发现抑制 SOCS1 可以减少气道上皮细胞中的铁死亡，并减轻 OVA 激发的野生型小鼠的气道高反应性（AHR），而 SOCS1 的过表达则加剧了 OVA 激发的 IL-13 敲除小鼠的上述反应。我们的研究结果揭示了 IL-13/STAT6/SOCS1/SLC7A11 通路是 2 型高反应性哮喘中铁死亡的一种新的分子机制，证实靶向气道上皮细胞中的铁死亡是治疗 2 型高反应性哮喘的一种潜在策略。
