反式-IL-6信号的上皮基因特征定义了2型低度哮喘亚群
2023/12/20
摘要
背景：哮喘可分为2型高炎症表型和2型低炎症表型。在开发靶向2型低炎症的药物方面取得了有限的成功。之前的研究已经将IL-6信号通路与重度哮喘联系起来。IL-6与可溶性IL-6Rα协同激活气道上皮细胞信号传导。
目的：我们试图研究sIL-6Rα扩增的IL-6信号在气道上皮细胞中的作用，并开发一种IL-6+ sIL-6Rα基因特征，用于选择可能对抗IL-6疗法有反应的哮喘患者。
方法：我们使用IL-6、sIL-6Rα以及抑制剂sgp130(奥兰基塞普，Olamkicept)和抗IL-6R(托珠单抗，Tocilizumab)联合刺激人气道上皮细胞，以评估对通路激活、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，我们建立了一个基因特征来识别IL-6高水平患者。
结果：与IL-6单独作用相比，sIL-6Rα增强了气道上皮细胞中IL-6通路的激活，表现为STAT3磷酸化增加和更强的基因诱导。Olamkicept和Tocilizumab抑制IL-6+sIL-6Rα对基因表达的影响。我们建立了一个IL-6 + sIL-6Rα基因特征，并观察到该基因特征在支气管活检组织中富集，而不是在哮喘患者的鼻刷中富集。IL-6+sIL-6Rα基因特征评分与哮喘患者痰嗜酸性粒细胞水平降低相关。
结论：sIL-6Rα可增强支气管上皮细胞的IL-6信号通路。痰嗜酸粒细胞减少的哮喘患者局部气道IL-6+sIL-6Rα信号增高。
An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma
Zaid W El-Husseini, Dmitry Khalenkow, Andy Lan et. Al
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.
OBJECTIVES: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: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.
CONCLUSIONS: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：哮喘可分为2型高炎症表型和2型低炎症表型。在开发靶向2型低炎症的药物方面取得了有限的成功。之前的研究已经将IL-6信号通路与重度哮喘联系起来。IL-6与可溶性IL-6Rα协同激活气道上皮细胞信号传导。
目的：我们试图研究sIL-6Rα扩增的IL-6信号在气道上皮细胞中的作用，并开发一种IL-6+ sIL-6Rα基因特征，用于选择可能对抗IL-6疗法有反应的哮喘患者。
方法：我们使用IL-6、sIL-6Rα以及抑制剂sgp130(奥兰基塞普，Olamkicept)和抗IL-6R(托珠单抗，Tocilizumab)联合刺激人气道上皮细胞，以评估对通路激活、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，我们建立了一个基因特征来识别IL-6高水平患者。
结果：与IL-6单独作用相比，sIL-6Rα增强了气道上皮细胞中IL-6通路的激活，表现为STAT3磷酸化增加和更强的基因诱导。Olamkicept和Tocilizumab抑制IL-6+sIL-6Rα对基因表达的影响。我们建立了一个IL-6 + sIL-6Rα基因特征，并观察到该基因特征在支气管活检组织中富集，而不是在哮喘患者的鼻刷中富集。IL-6+sIL-6Rα基因特征评分与哮喘患者痰嗜酸性粒细胞水平降低相关。
结论：sIL-6Rα可增强支气管上皮细胞的IL-6信号通路。痰嗜酸粒细胞减少的哮喘患者局部气道IL-6+sIL-6Rα信号增高。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Respir Res. 2023 Dec 7;24(1):308 DOI: 10.1186/s12931-023-02617-w）
（Respir Res. 2023 Dec 7;24(1):308 DOI: 10.1186/s12931-023-02617-w）
An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma
Zaid W El-Husseini, Dmitry Khalenkow, Andy Lan et. Al
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.
OBJECTIVES: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: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.
CONCLUSIONS: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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烟酰胺单核苷酸通过抑制SIRT3 SUMO化减轻哮喘气道上皮屏障功能障碍
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