Protein disulfide isomerase-endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness.
Protein disulfide isomerase-endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness.
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DOI：
10.1016/j.jaci.2015.08.018
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Anathy V
中科院分区：
文献类型：
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作者：
Hoffman SM;Chapman DG;Lahue KG;Cahoon JM;Rattu GK;Daphtary N;Aliyeva M;Fortner KA;Erzurum SC;Comhair SA;Woodruff PG;Bhakta N;Dixon AE;Irvin CG;Janssen-Heininger YM;Poynter ME;Anathy V
哮喘和未折叠蛋白反应(UPR)之间存在关联的证据正在出现。ERp57是一种内质网定位的氧化还原伴侣，参与糖蛋白的折叠和分泌。我们之前已经证明，ERp57在过敏原挑战的人和小鼠肺上皮细胞中上调。然而，ERp57在哮喘病理生理学中的作用尚不清楚。在这里，我们试图研究呼吸道上皮细胞特异性ERp57在过敏性哮喘发病机制中的作用。我们检测了ERp57在人哮喘呼吸道上皮中的表达，并利用过敏性哮喘的小鼠模型来评估上皮特异性ERp57的相关性。哮喘者和非哮喘者的肺活检显示哮喘上皮中ERp57的表达显著增加。在过敏性哮喘的小鼠模型中，ERp57的缺失导致炎症细胞和呼吸道阻力显著降低。我们进一步观察到，在HDM攻击的ERp57缺失小鼠的肺中，嗜酸性粒细胞趋化蛋白、EGF和Periostin中的二硫键也减少了。α基因缺失的小鼠肺组织中的纤维化标志物，如胶原和ERP57SMA也显著减少。此外，适应性免疫反应对于HDM诱导的内质网应激和呼吸道纤维化是必不可少的。在这里，我们显示ERp57在哮喘患者和过敏性呼吸道疾病小鼠的呼吸道上皮细胞中增加。ERp57的增加与促炎症、凋亡和纤维化介质的氧化还原修饰有关，并导致呼吸道高反应性(AHR)。在呼吸道上皮特异性抑制ERp57的策略可能为缓解过敏性哮喘的表型提供了机会。
Evidence for association between asthma and the unfolded protein response (UPR) is emerging. ERp57 is an ER localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is up regulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown. Here, we sought to examine the contribution of airway epithelial-specific ERp57 in the pathogenesis of allergic asthma. We examined the expression of ERp57 in human asthmatic airway epithelium and utilized murine models of allergic asthma to evaluate the relevance of epithelial- specific ERp57. Lung biopsies from asthmatics and non-asthmatics revealed a predominant increase in ERp57 in asthmatic epithelium. Deletion of ERp57 resulted in a significant decreases in the inflammatory cells and airways resistance in a murine model of allergic asthma. We further observed that disulfide bridges in eotaxin, EGF and periostin were also decreased in the lungs of HDM-challenged ERp57 deleted mice. Fibrotic markers such as collagen and αSMA were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for HDM-induced ER stress and airways fibrosis. Here we show that ERp57 is increased in the airway epithelium of asthmatics and in mice with allergic airways disease. ERp57 increase is associated with redox modification of pro- inflammatory, apoptotic and fibrotic mediators, and contribute to airways hyperresposiveness (AHR). The strategies to inhibit ERp57 specifically within the airways epithelium may provide an opportunity to alleviate allergic asthma phenotype.