GSDMB induces an asthma phenotype characterized by increased airway responsiveness and remodeling without lung inflammation
GSDMB induces an asthma phenotype characterized by increased airway responsiveness and remodeling without lung inflammation
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DOI：
10.1073/pnas.1610433113
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发表时间：
2016-11-15
影响因子：
11.1
通讯作者：
Broide, David H.
中科院分区：
文献类型：
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作者：
Das, Sudipta;Miller, Marina;Broide, David H.
染色体 17q21 上的 Gasdermin B (GSDMB) 与哮喘有很强的遗传联系，但其在哮喘中的功能尚不清楚。在这里，我们发现 GSDMB 在人类哮喘的肺支气管上皮中高表达。 GSDMB 在原代人支气管上皮中的过度表达增加了对气道重塑 [TGF-β 1, 5-脂氧合酶 (5-LO)] 和气道高反应性 (AHR) (5-LO) 重要的基因的表达。有趣的是，表达增加水平的人GSDMB转基因的hGSDMB(Zp3-Cre)小鼠表现出AHR显着自发增加和气道重塑显着自发增加，在没有气道炎症的情况下平滑肌质量增加和纤维化增加。此外，hGSDMB(Zp3-Cre)小鼠表现出与体外在过表达GSDMB的上皮细胞中观察到的相同的重塑和AHR介质(TGF-β1、5-LO)的增加。 GSDMB 通过诱导 5-LO 来诱导 TGF-β 1 表达，因为在过表达 GSDMB 的上皮细胞中敲除 5-LO 会抑制 TGF-β 1 表达。这些研究表明，GSDMB 是一种与哮喘高度相关的基因，但其在哮喘中的功能以前未知，它通过以前未被识别的途径（其中 GSDMB 诱导 5-LO 诱导支气管上皮中的 TGF-β1）调节 AHR 和气道重塑，而不会引起气道炎症。
Gasdermin B (GSDMB) on chromosome 17q21 demonstrates a strong genetic linkage to asthma, but its function in asthma is unknown. Here we identified that GSDMB is highly expressed in lung bronchial epithelium in human asthma. Overexpression of GSDMB in primary human bronchial epithelium increased expression of genes important to both airway remodeling [TGF-beta 1, 5-lipoxygenase (5-LO)] and airway-hyperresponsiveness (AHR) (5-LO). Interestingly, hGSDMB(Zp3-Cre) mice expressing increased levels of the human GSDMB transgene showed a significant spontaneous increase in AHR and a significant spontaneous increase in airway remodeling, with increased smooth muscle mass and increased fibrosis in the absence of airway inflammation. In addition, hGSDMB(Zp3-Cre) mice showed increases in the same remodeling and AHR mediators (TGF-beta 1, 5-LO) observed in vitro in GSDMB-overexpressing epithelial cells. GSDMB induces TGF-beta 1 expression via induction of 5-LO, because knockdown of 5-LO in epithelial cells over-expressing GSDMB inhibited TGF-beta 1 expression. These studies demonstrate that GSDMB, a gene highly linked to asthma but whose function in asthma is previously unknown, regulates AHR and airway remodeling without airway inflammation through a previously unrecognized pathway in which GSDMB induces 5-LO to induce TGF-beta 1 in bronchial epithelium.