表皮生长因子受体参与IL-13介导的皮质类固醇抵抗的气道炎症
2020/03/11
摘要
背景：严重哮喘的有效治疗尚未完全实现。虽然由2型细胞因子引起的嗜酸性粒细胞炎症对皮质类固醇和生物疗法有反应，但很多重症哮喘患者表现为对皮质类固醇无反应的混合性粒细胞炎症。
目的：验证促过敏细胞因子IL-13可以同时驱动皮质类固醇敏感和皮质类固醇抵抗反应的假设。
结果：通过整合IL-13诱导炎症的体内外模型，我们确定了表皮生长因子受体（EGFR/ERBB1）介导的IL-13在皮质类固醇抵抗和支气管高反应性（BHR）中的作用。利用U-BIOPRED队列中的人类上皮转录组数据进行拓扑数据分析，确定严重哮喘组的特征与IL-13和EGFR/ERBB激活的存在一致，并涉及不同的EGFR配体。我们的数据表明，IL-13可能在严重哮喘中发挥双重作用：一方面驱动病理性皮质类固醇抵抗的混合粒细胞性炎症，另一方面支持有益的上皮修复反应，这可能会混淆临床试验中的反应。
结论和临床相关性：详细分析IL-13的下游分子通路，并利用ERBB受体和配体家族驱动皮质类固醇抵抗型炎症。应加强针对难治性哮喘亚型的新治疗方法的开发。
Involvement of the Epidermal Growth Factor Receptor in IL-13 Mediated, Corticosteroid-Resistant Airway Inflammation.
Davies ER, Perotin JM, Kelly JFC, Djukanovic R, Davies DE1, Haitchi HM; U-BIOPRED Study Group.
Abstract
BACKGROUND: Effective treatment for severe asthma is a significant unmet need. While eosinophilic inflammation caused by Type 2 cytokines is responsive to corticosteroid and biologic therapies, many severe asthmatics exhibit corticosteroid-unresponsive mixed granulocytic inflammation.
OBJECTIVE: Here, we tested the hypothesis that the pro-allergic cytokine, IL-13, can drive both corticosteroid-sensitive and corticosteroid-resistant responses.
RESULTS: By integration of in vivo and in vitro models of IL-13 driven inflammation, we identify a role for the epidermal growth factor receptor (EGFR/ERBB1) as a mediator of corticosteroid-unresponsive inflammation and bronchial hyperresponsiveness (BHR) driven by IL-13. Topological data analysis using human epithelial transcriptomic data from the U-BIOPRED cohort identified severe asthma groups with features consistent with the presence of IL-13 and EGFR/ERBB activation, with involvement of distinct EGFR ligands. Our data suggest that IL-13 may play a dual role in severe asthma: on the one hand driving pathologic corticosteroid-refractory mixed granulocytic inflammation, but on the other hand underpinning beneficial epithelial repair responses, which may confound responses in clinical trials.
CONCLUSION AND CLINICAL RELEVANCE: Detailed dissection of those molecular pathways that are downstream of IL-13 and utilize the ERBB receptor and ligand family to drive corticosteroid refractory inflammation should enhance the development of new treatments that target this sub-phenotype(s) of severe asthma, where there is an unmet need.
背景：严重哮喘的有效治疗尚未完全实现。虽然由2型细胞因子引起的嗜酸性粒细胞炎症对皮质类固醇和生物疗法有反应，但很多重症哮喘患者表现为对皮质类固醇无反应的混合性粒细胞炎症。
目的：验证促过敏细胞因子IL-13可以同时驱动皮质类固醇敏感和皮质类固醇抵抗反应的假设。
结果：通过整合IL-13诱导炎症的体内外模型，我们确定了表皮生长因子受体（EGFR/ERBB1）介导的IL-13在皮质类固醇抵抗和支气管高反应性（BHR）中的作用。利用U-BIOPRED队列中的人类上皮转录组数据进行拓扑数据分析，确定严重哮喘组的特征与IL-13和EGFR/ERBB激活的存在一致，并涉及不同的EGFR配体。我们的数据表明，IL-13可能在严重哮喘中发挥双重作用：一方面驱动病理性皮质类固醇抵抗的混合粒细胞性炎症，另一方面支持有益的上皮修复反应，这可能会混淆临床试验中的反应。
结论和临床相关性：详细分析IL-13的下游分子通路，并利用ERBB受体和配体家族驱动皮质类固醇抵抗型炎症。应加强针对难治性哮喘亚型的新治疗方法的开发。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Clin Exp Allergy. 2020 Feb 24. doi: 10.1111/cea.13591.)
(Clin Exp Allergy. 2020 Feb 24. doi: 10.1111/cea.13591.)
Involvement of the Epidermal Growth Factor Receptor in IL-13 Mediated, Corticosteroid-Resistant Airway Inflammation.
Davies ER, Perotin JM, Kelly JFC, Djukanovic R, Davies DE1, Haitchi HM; U-BIOPRED Study Group.
Abstract
BACKGROUND: Effective treatment for severe asthma is a significant unmet need. While eosinophilic inflammation caused by Type 2 cytokines is responsive to corticosteroid and biologic therapies, many severe asthmatics exhibit corticosteroid-unresponsive mixed granulocytic inflammation.
OBJECTIVE: Here, we tested the hypothesis that the pro-allergic cytokine, IL-13, can drive both corticosteroid-sensitive and corticosteroid-resistant responses.
RESULTS: By integration of in vivo and in vitro models of IL-13 driven inflammation, we identify a role for the epidermal growth factor receptor (EGFR/ERBB1) as a mediator of corticosteroid-unresponsive inflammation and bronchial hyperresponsiveness (BHR) driven by IL-13. Topological data analysis using human epithelial transcriptomic data from the U-BIOPRED cohort identified severe asthma groups with features consistent with the presence of IL-13 and EGFR/ERBB activation, with involvement of distinct EGFR ligands. Our data suggest that IL-13 may play a dual role in severe asthma: on the one hand driving pathologic corticosteroid-refractory mixed granulocytic inflammation, but on the other hand underpinning beneficial epithelial repair responses, which may confound responses in clinical trials.
CONCLUSION AND CLINICAL RELEVANCE: Detailed dissection of those molecular pathways that are downstream of IL-13 and utilize the ERBB receptor and ligand family to drive corticosteroid refractory inflammation should enhance the development of new treatments that target this sub-phenotype(s) of severe asthma, where there is an unmet need.
