嗜酸性粒细胞衍生的白细胞介素-24破坏上皮完整性并加重过敏性哮喘小鼠模型的气道重塑
2025/10/31
摘要
哮喘是一种异质性疾病，其特征是免疫细胞浸润，这些免疫细胞与上皮细胞相互作用，并释放各种驱动慢性炎症和气道重塑的因子。尽管基于单克隆抗体的生物制剂可减轻炎症，但它们在抑制气道重塑方面的疗效有限。白细胞介素 - 24（IL - 24）与中性粒细胞性哮喘有关，但其在嗜酸性粒细胞性哮喘中的作用仍不清楚。在这里，我们发现IL - 24主要由卵清蛋白（OVA）和屋尘螨（HDM）诱导的哮喘样肺部疾病模型小鼠中浸润的嗜酸性粒细胞分泌。IL - 24敲除小鼠的炎症反应减轻，肺纤维化缓解，上皮完整性改善，黏液过度分泌减少。从机制上讲，IL - 24激活CXCL5/CXCR1/CXCR2轴，增强嗜酸性粒细胞向肺部的募集。IL - 24破坏上皮紧密连接的完整性，导致通透性增加。此外，IL - 24作用于气道上皮细胞，促进上皮 - 间质转化（EMT）样改变以及促纤维化介质的分泌，从而导致支气管壁增厚和肺纤维化。因此，靶向IL - 24有望通过抑制炎症和病理重塑来进行抗哮喘干预。
Eosinophil-derived interleukin-24 compromises epithelial integrity and aggravates airway remodeling in mouse models of allergic asthma
Yi-Rou Wu, Chung-Hsi Hsing, Chiao-Juno Chiu, Bor-Luen Chiang, Yu-Hsiang Hsu
Abstract
Asthma is a heterogeneous disease characterized by infiltration of immune cells that interact with epithelial cells and release various factors driving chronic inflammation and airway remodeling. Although monoclonal antibody-based biologics alleviate inflammation, their efficacy in suppressing airway remodeling is limited. Interleukin-24 (IL-24) has been implicated in neutrophilic asthma, but its role in eosinophilic asthma remains unclear. Here, we show that IL-24 is mainly secreted by infiltrating eosinophils in mice with OVA- and HDM-induced asthma-like lung disease models. IL-24 knockout mice exhibit reduced inflammatory responses, alleviated pulmonary fibrosis, improved epithelial integrity, and decreased mucus hypersecretion. Mechanistically, IL-24 activates the CXCL5/CXCR1/CXCR2 axis, enhancing eosinophil recruitment to the lungs. IL-24 disrupts epithelial tight junction integrity, contributing to increased permeability. Furthermore, IL-24 targets airway epithelial cells, promoting EMT-like changes and the secretion of profibrotic mediators, which leads to bronchial wall thickening and pulmonary fibrosis. Therefore, targeting IL-24 holds promise for anti-asthmatic interventions by suppressing inflammation and pathological remodeling.
哮喘是一种异质性疾病，其特征是免疫细胞浸润，这些免疫细胞与上皮细胞相互作用，并释放各种驱动慢性炎症和气道重塑的因子。尽管基于单克隆抗体的生物制剂可减轻炎症，但它们在抑制气道重塑方面的疗效有限。白细胞介素 - 24（IL - 24）与中性粒细胞性哮喘有关，但其在嗜酸性粒细胞性哮喘中的作用仍不清楚。在这里，我们发现IL - 24主要由卵清蛋白（OVA）和屋尘螨（HDM）诱导的哮喘样肺部疾病模型小鼠中浸润的嗜酸性粒细胞分泌。IL - 24敲除小鼠的炎症反应减轻，肺纤维化缓解，上皮完整性改善，黏液过度分泌减少。从机制上讲，IL - 24激活CXCL5/CXCR1/CXCR2轴，增强嗜酸性粒细胞向肺部的募集。IL - 24破坏上皮紧密连接的完整性，导致通透性增加。此外，IL - 24作用于气道上皮细胞，促进上皮 - 间质转化（EMT）样改变以及促纤维化介质的分泌，从而导致支气管壁增厚和肺纤维化。因此，靶向IL - 24有望通过抑制炎症和病理重塑来进行抗哮喘干预。
（北京朝阳医院呼吸与危重症医学科 顾宪民 摘译）
（中日友好医院呼吸与危重症医学科 林江涛 审校）
（Nat Commun. 2025 Oct 20;16(1):9248. doi: 10.1038/s41467-025-64302-4.）
（中日友好医院呼吸与危重症医学科 林江涛 审校）
（Nat Commun. 2025 Oct 20;16(1):9248. doi: 10.1038/s41467-025-64302-4.）
Eosinophil-derived interleukin-24 compromises epithelial integrity and aggravates airway remodeling in mouse models of allergic asthma
Yi-Rou Wu, Chung-Hsi Hsing, Chiao-Juno Chiu, Bor-Luen Chiang, Yu-Hsiang Hsu
Abstract
Asthma is a heterogeneous disease characterized by infiltration of immune cells that interact with epithelial cells and release various factors driving chronic inflammation and airway remodeling. Although monoclonal antibody-based biologics alleviate inflammation, their efficacy in suppressing airway remodeling is limited. Interleukin-24 (IL-24) has been implicated in neutrophilic asthma, but its role in eosinophilic asthma remains unclear. Here, we show that IL-24 is mainly secreted by infiltrating eosinophils in mice with OVA- and HDM-induced asthma-like lung disease models. IL-24 knockout mice exhibit reduced inflammatory responses, alleviated pulmonary fibrosis, improved epithelial integrity, and decreased mucus hypersecretion. Mechanistically, IL-24 activates the CXCL5/CXCR1/CXCR2 axis, enhancing eosinophil recruitment to the lungs. IL-24 disrupts epithelial tight junction integrity, contributing to increased permeability. Furthermore, IL-24 targets airway epithelial cells, promoting EMT-like changes and the secretion of profibrotic mediators, which leads to bronchial wall thickening and pulmonary fibrosis. Therefore, targeting IL-24 holds promise for anti-asthmatic interventions by suppressing inflammation and pathological remodeling.
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高血清TSLP是迟发型、长病程嗜酸性粒细胞性哮喘的特征
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胃食管反流病与哮喘之间的遗传重叠和因果关系分析
