EGFR activation-induced decreases in claudin1 promote MUC5AC expression and exacerbate asthma in mice
EGFR activation-induced decreases in claudin1 promote MUC5AC expression and exacerbate asthma in mice
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DOI：
10.1038/s41385-020-0272-z
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发表时间：
2020-03-04
影响因子：
8
通讯作者：
Hong, Min
中科院分区：
文献类型：
--
作者：
Jia, Zhirong;Bao, Kaifan;Hong, Min
Claudin1在维持上皮屏障中起重要作用，而由表皮生长因子受体(EGFR)激活引起的粘液高分泌是哮喘的重要病理特征。Claudin1的表达与粘液高分泌和EGFR激活之间的关系仍不清楚。在这份报告中，我们发现Claudin1的表达与哮喘分期有关，在哮喘患者和屋尘螨(HDM)诱导的小鼠哮喘模型中都是如此。Claudin1基因敲除可诱导MUC5AC在16HBE细胞和小鼠呼吸道中过表达。此外，Claudin1的表达与哮喘的严重程度呈负相关，表现为MUC5AC的表达显著增加，更严重的气道炎症，以及HDM攻击后Claudin1基因敲除的小鼠肺内的气道高反应性增加。在体外和体内，EGFR的激活降低了claudin1的表达，增加了MUC5AC的表达。厄洛替尼可减轻小鼠过敏性气道炎症，恢复Claudin1的表达，降低MUC5AC的表达。这些结果提示，EGFR激活诱导的claudin1表达减少促进杯状细胞化生，通过EGFR拮抗恢复claudin1的屏障完整性，可能为哮喘的治疗提供新的策略。
Claudin1 plays a critical role in maintaining the epithelial barrier, and mucus hypersecretion induced by epidermal growth factor receptor (EGFR) activation is a pivotal pathological feature of asthma. The relationship between claudin1 expression and mucus hypersecretion and EGFR activation is still poorly understood. In this report, we showed that claudin1 expression correlated with asthma stage, in both patients with asthma and in the house dust mite (HDM)-induced mouse asthma model. Claudin1 knockdown induced MUC5AC overexpression both in 16HBE cells and in mouse airways. In addition, claudin1 expression negatively correlated with asthma severity as demonstrated by significantly higher MUC5AC expression, more severe airway inflammation, and increased airway hyperreactivity in mouse lungs with claudin1 knockdown following HDM challenge. EGFR activation reduced claudin1 expression and increased MUC5AC expression, both in vitro and in vivo. Erlotinib alleviated murine allergic airway inflammation, restored claudin1 expression and decreased MUC5AC expression. These results suggest that EGFR activation-induced decreases in claudin1 promote goblet-cell metaplasia, and restoring claudin1 to maintain barrier integrity by EGFR antagonism may provide a novel therapeutic strategy for asthma.