肠凝集素-1基因的一种常见多态性对重度哮喘患者的黏液堵塞的影响
2024/05/28
摘要
本研究旨在探讨肠凝集素-1 (ITLN-1)在哮喘病理性气道黏液形成中的分子作用及临床意义。通过对人气道上皮细胞的分析，我们发现在一组化生性MUC5AC+黏液分泌细胞中，白细胞介素-13 (IL-13)高度诱导ITLN1基因的表达，并且ITLN-1蛋白是IL-13诱导的黏液分泌的一种分泌成分。此外，我们发现ITLN-1蛋白与MUC5AC黏蛋白的c端结合，其在气道上皮细胞中的缺失部分逆转了IL -13诱导的黏膜稳定。通过对鼻气道上皮刷的分析，我们发现与低T2的儿童相比，ITLN1在高T2的哮喘患儿中高表达。此外，我们证明了ITLN-1基因表达和蛋白水平显著降低，这是一种常见的基因变异，与高T2哮喘中黏液栓形成的保护相关。这项工作确定了哮喘黏液阻塞治疗的重要生物标志物和可靶向通路。
A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma
Jamie L Everman, Satria P Sajuthi, Maude A Liegeois, Nathan D Jackson, Erik H Collet, Michael C Peters, Maurizio Chioccioli, Camille M Moore, Bhavika B Patel, Nathan Dyjack, et al.
Abstract
By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.
本研究旨在探讨肠凝集素-1 (ITLN-1)在哮喘病理性气道黏液形成中的分子作用及临床意义。通过对人气道上皮细胞的分析，我们发现在一组化生性MUC5AC+黏液分泌细胞中，白细胞介素-13 (IL-13)高度诱导ITLN1基因的表达，并且ITLN-1蛋白是IL-13诱导的黏液分泌的一种分泌成分。此外，我们发现ITLN-1蛋白与MUC5AC黏蛋白的c端结合，其在气道上皮细胞中的缺失部分逆转了IL -13诱导的黏膜稳定。通过对鼻气道上皮刷的分析，我们发现与低T2的儿童相比，ITLN1在高T2的哮喘患儿中高表达。此外，我们证明了ITLN-1基因表达和蛋白水平显著降低，这是一种常见的基因变异，与高T2哮喘中黏液栓形成的保护相关。这项工作确定了哮喘黏液阻塞治疗的重要生物标志物和可靶向通路。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Nat Commun. 2024 May 9;15(1):3900. doi: 10.1038/s41467-024-48034-5.)
(Nat Commun. 2024 May 9;15(1):3900. doi: 10.1038/s41467-024-48034-5.)
A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma
Jamie L Everman, Satria P Sajuthi, Maude A Liegeois, Nathan D Jackson, Erik H Collet, Michael C Peters, Maurizio Chioccioli, Camille M Moore, Bhavika B Patel, Nathan Dyjack, et al.
Abstract
By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.
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通过多个数据集探索哮喘的分子机制
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下调otulin可诱导中性粒细胞性哮喘炎症小体活化
