PDF(Pubmed)
Abstract：
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.
摘要：
高Th2型哮喘的特征是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一直在增加。Ferroptosis,最近发现的一种程序性细胞死亡，参与Th2型高哮喘的病理过程；然而，潜在的机制仍未完全理解。在这项研究中,我们证明了血清丙二醛（MDA）水平，脂质过氧化的指标，在哮喘患者中，与IL-13水平呈正相关，与预测的1s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，显示IL-13通过上调细胞因子信号抑制因子1（SOCS1）促进铁凋亡，人类气道类器官，和卵清蛋白（OVA）激发的哮喘模型。我们确定了信号转导和转录激活因子6（STAT6）在IL-13刺激后促进SOCS1的转录。此外，SOCS1，一种E3泛素连接酶，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的铁凋亡。最后,我们发现，抑制SOCS1可以降低气道上皮细胞的铁凋亡，减轻OVA攻击的宽型小鼠的气道高反应性（AHR），而SOCS1的过表达在OVA攻击的IL-13敲除小鼠中加剧了上述情况。我们的发现揭示了IL-13/STAT6/SOCS1/SLC7A11通路是Th2型高哮喘中铁凋亡的新分子机制。证实靶向气道上皮细胞的铁凋亡是Th2高哮喘的潜在治疗策略。
