反式-IL-6 信号的上皮基因特征定义了 2 型低度哮喘亚群
2024/01/26
摘要
背景：哮喘被分为类型2高和类型2低的炎症表型。在开发针对类型2低炎症的药物方面取得了有限的成果。先前的研究将IL-6信号与严重哮喘联系起来。IL-6与可溶性IL-6Rα协同作用，激活气道上皮的细胞信号。
目的：我们旨在研究sIL-6Rα放大的IL-6信号在气道上皮中的作用，并制定一个IL-6 + sIL-6Rα基因特征，该特征可用于选择可能对抗IL-6治疗有响应的哮喘患者。
方法：用IL-6、sIL-6Rα和抑制剂（sgp130，Olamkicept）以及抗IL-6R（Tocilizumab）的组合刺激人气道上皮细胞，评估对通路激活、上皮屏障完整性和基因表达的影响。通过支气管活检和鼻刷生成基因特征，以识别IL-6高表达的患者。
结果：可溶性IL-6Rα放大了IL-6通路的激活，表现为相比仅用IL-6，气道上皮细胞中STAT3磷酸化的增加和更强的基因诱导。Olamkicept和Tocilizumab抑制了IL-6 + sIL-6Rα对基因表达的影响。我们制定了一个IL-6 + sIL-6Rα基因特征，并观察到这个特征在哮喘患者的支气管活检样本中富集，而在健康对照组中富集于鼻黏膜刷取样本。在哮喘中，IL-6 + sIL-6Rα基因特征评分与痰液嗜酸性粒细胞水平较低相关。
结论：sIL-6Rα在支气管上皮细胞中放大了IL-6信号。在嗜酸性粒细胞水平较低的哮喘患者中观察到更高局部气道IL-6 + sIL-6Rα信号。
An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma
El-Husseini ZW, Khalenkow D, Lan A, van der Molen T, Brightling C, Papi A, Rabe KF, Siddiqui S, Singh D, Kraft M, Beghe B, van den Berge M, van Gosliga D, Nawijn MC, Rose-John S, Koppelman GH, Gosens R
Abstract
Background:Asthma is stratified into type 2-high and type 2-low inflammatory phenotypes. Limited success has been achieved in developing drugs that target type 2-low inflammation. Previous studies have linked IL-6 signaling to severe asthma. IL-6 cooperates with soluble-IL-6Rα to activate cell signaling in airway epithelium.
Objective:We sought to study the role of sIL-6Rα amplified IL-6 signaling in airway epithelium and to develop an IL-6+ sIL-6Rα gene signature that may be used to select asthma patients who potentially respond to anti-IL-6 therapy.
Methods:Human airway epithelial cells were stimulated with combinations of IL-6, sIL-6Rα, and inhibitors, sgp130 (Olamkicept), and anti-IL-6R (Tocilizumab), to assess effects on pathway activation, epithelial barrier integrity, and gene expression. A gene signature was generated to identify IL-6 high patients using bronchial biopsies and nasal brushes.
Results:Soluble-IL-6Rα amplified the activation of the IL-6 pathway, shown by the increase of STAT3 phosphorylation and stronger gene induction in airway epithelial cells compared to IL-6 alone. Olamkicept and Tocilizumab inhibited the effect of IL-6 + sIL-6Rα on gene expression. We developed an IL-6 + sIL-6Rα gene signature and observed enrichment of this signature in bronchial biopsies but not nasal brushes from asthma patients compared to healthy controls. An IL-6 + sIL-6Rα gene signature score was associated with lower levels of sputum eosinophils in asthma.
Conclusion:sIL-6Rα amplifies IL-6 signaling in bronchial epithelial cells. Higher local airway IL-6 + sIL-6Rα signaling is observed in asthma patients with low sputum eosinophils.
背景：哮喘被分为类型2高和类型2低的炎症表型。在开发针对类型2低炎症的药物方面取得了有限的成果。先前的研究将IL-6信号与严重哮喘联系起来。IL-6与可溶性IL-6Rα协同作用，激活气道上皮的细胞信号。
目的：我们旨在研究sIL-6Rα放大的IL-6信号在气道上皮中的作用，并制定一个IL-6 + sIL-6Rα基因特征，该特征可用于选择可能对抗IL-6治疗有响应的哮喘患者。
方法：用IL-6、sIL-6Rα和抑制剂（sgp130，Olamkicept）以及抗IL-6R（Tocilizumab）的组合刺激人气道上皮细胞，评估对通路激活、上皮屏障完整性和基因表达的影响。通过支气管活检和鼻刷生成基因特征，以识别IL-6高表达的患者。
结果：可溶性IL-6Rα放大了IL-6通路的激活，表现为相比仅用IL-6，气道上皮细胞中STAT3磷酸化的增加和更强的基因诱导。Olamkicept和Tocilizumab抑制了IL-6 + sIL-6Rα对基因表达的影响。我们制定了一个IL-6 + sIL-6Rα基因特征，并观察到这个特征在哮喘患者的支气管活检样本中富集，而在健康对照组中富集于鼻黏膜刷取样本。在哮喘中，IL-6 + sIL-6Rα基因特征评分与痰液嗜酸性粒细胞水平较低相关。
结论：sIL-6Rα在支气管上皮细胞中放大了IL-6信号。在嗜酸性粒细胞水平较低的哮喘患者中观察到更高局部气道IL-6 + sIL-6Rα信号。
(中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校)
(Respir Res. 2023 Dec 7. DOI: 10.1186/s12931-023-02617-w)
(Respir Res. 2023 Dec 7. DOI: 10.1186/s12931-023-02617-w)
An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma
El-Husseini ZW, Khalenkow D, Lan A, van der Molen T, Brightling C, Papi A, Rabe KF, Siddiqui S, Singh D, Kraft M, Beghe B, van den Berge M, van Gosliga D, Nawijn MC, Rose-John S, Koppelman GH, Gosens R
Abstract
Background:Asthma is stratified into type 2-high and type 2-low inflammatory phenotypes. Limited success has been achieved in developing drugs that target type 2-low inflammation. Previous studies have linked IL-6 signaling to severe asthma. IL-6 cooperates with soluble-IL-6Rα to activate cell signaling in airway epithelium.
Objective:We sought to study the role of sIL-6Rα amplified IL-6 signaling in airway epithelium and to develop an IL-6+ sIL-6Rα gene signature that may be used to select asthma patients who potentially respond to anti-IL-6 therapy.
Methods:Human airway epithelial cells were stimulated with combinations of IL-6, sIL-6Rα, and inhibitors, sgp130 (Olamkicept), and anti-IL-6R (Tocilizumab), to assess effects on pathway activation, epithelial barrier integrity, and gene expression. A gene signature was generated to identify IL-6 high patients using bronchial biopsies and nasal brushes.
Results:Soluble-IL-6Rα amplified the activation of the IL-6 pathway, shown by the increase of STAT3 phosphorylation and stronger gene induction in airway epithelial cells compared to IL-6 alone. Olamkicept and Tocilizumab inhibited the effect of IL-6 + sIL-6Rα on gene expression. We developed an IL-6 + sIL-6Rα gene signature and observed enrichment of this signature in bronchial biopsies but not nasal brushes from asthma patients compared to healthy controls. An IL-6 + sIL-6Rα gene signature score was associated with lower levels of sputum eosinophils in asthma.
Conclusion:sIL-6Rα amplifies IL-6 signaling in bronchial epithelial cells. Higher local airway IL-6 + sIL-6Rα signaling is observed in asthma patients with low sputum eosinophils.
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重度和非重度哮喘中炎症小体反应的特征和抑制
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SYVN1通过促进SIRT2泛素化降解在哮喘气道重塑中起保护作用
