IL-13 facilitates ferroptotic death in asthmatic epithelial cells via SOCS1-mediated ubiquitinated degradation of SLC7A11

细胞因子信号抑制因子1 细胞生物学 细胞因子 免疫学 泛素 STAT6 呼吸上皮 化学 癌症研究 生物 医学 白细胞介素4 上皮 基因 生物化学 抑制器 病理
作者
Manli Miao,Min Pan,Xu Chen,Jiapan Shen,Ling Zhang,Xiaoxia Feng,Mengting Chen,Guofeng Cui,Huaiyuan Zong,Wen Zhang,Shuang Chang,Fangzhou Xu,Zixi Wang,Dapeng Li,Weiwei Liu,Ding Zhao,Shengquan Zhang,Biao Chen,Xiaojun Zha,Xiaoyun Fan
出处
期刊:Redox biology [Elsevier]
卷期号:71: 103100-103100 被引量:3
标识
DOI:10.1016/j.redox.2024.103100
摘要

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.
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