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Exendin-4 restores airway mucus homeostasis through the GLP1R-PKA-PPARγ-FOXA2-phosphatase signaling.
Mucosal Immunology ( IF 7.9 ) Pub Date : 2020-02-07 , DOI: 10.1038/s41385-020-0262-1 Woosuk Choi 1 , Shawn Choe 1 , Jingjun Lin 1 , Michael T Borchers 2, 3 , Beata Kosmider 4, 5, 6 , Robert Vassallo 7 , Andrew H Limper 7 , Gee W Lau 1
Mucosal Immunology ( IF 7.9 ) Pub Date : 2020-02-07 , DOI: 10.1038/s41385-020-0262-1 Woosuk Choi 1 , Shawn Choe 1 , Jingjun Lin 1 , Michael T Borchers 2, 3 , Beata Kosmider 4, 5, 6 , Robert Vassallo 7 , Andrew H Limper 7 , Gee W Lau 1
Affiliation
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Goblet cell hyperplasia and metaplasia and excessive mucus are prominent pathologies of chronic airway diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and chronic bronchitis. Chronic infection by respiratory pathogens, including Pseudomonas aeruginosa, exacerbates cyclical proinflammatory responses and mucus hypersecretion. P. aeruginosa and its virulence factor pyocyanin contribute to these pathologies by inhibiting FOXA2, a key transcriptional regulator of mucus homeostasis, through activation of antagonistic signaling pathways EGFR-AKT/ERK1/2 and IL-4/IL-13-STAT6-SPDEF. However, FOXA2-targeted therapy has not been previously explored. Here, we examined the feasibility of repurposing the incretin mimetic Exendin-4 to restore FOXA2-mediated airway mucus homeostasis. We have found that Exendin-4 restored FOXA2 expression, attenuated mucin production in COPD and CF-diseased airway cells, and reduced mucin and P. aeruginosa burden in mouse lungs. Mechanistically, Exendin-4 activated the GLP1R-PKA-PPAR-γ-dependent phosphatases PTEN and PTP1B, which inhibited key kinases within both EGFR and STAT6 signaling cascades. Our results may lead to the repurposing of Exendin-4 and other incretin mimetics to restore FOXA2 function and ultimately regulate excessive mucus in diseased airways.
中文翻译：
Exendin-4 通过 GLP1R-PKA-PPARγ-FOXA2-磷酸酶信号转导恢复气道粘液稳态。
杯状细胞增生和化生以及粘液过多是慢性气道疾病的突出病理，例如慢性阻塞性肺病（COPD）、囊性纤维化（CF）和慢性支气管炎。呼吸道病原体（包括铜绿假单胞菌）的慢性感染会加剧周期性促炎反应和粘液分泌过多。铜绿假单胞菌及其毒力因子绿脓素通过激活拮抗信号通路 EGFR-AKT/ERK1/2 和 IL-4/IL-13-STAT6-SPDEF 来抑制粘液稳态的关键转录调节因子 FOXA2，从而导致这些病理。然而，之前尚未探索过 FOXA2 靶向治疗。在这里，我们研究了重新利用肠促胰岛素模拟物 Exendin-4 以恢复 FOXA2 介导的气道粘液稳态的可行性。我们发现 Exendin-4 恢复了 FOXA2 表达，减弱了 COPD 和 CF 患病气道细胞中粘蛋白的产生，并减少了小鼠肺中的粘蛋白和铜绿假单胞菌负荷。从机制上讲，Exendin-4 激活了 GLP1R-PKA-PPAR-γ 依赖性磷酸酶 PTEN 和 PTP1B，它们抑制了 EGFR 和 STAT6 信号级联中的关键激酶。我们的结果可能会导致重新利用 Exendin-4 和其他肠促胰岛素模拟物以恢复 FOXA2 功能并最终调节患病气道中过多的粘液。
更新日期：2020-02-07
中文翻译：
Exendin-4 通过 GLP1R-PKA-PPARγ-FOXA2-磷酸酶信号转导恢复气道粘液稳态。
杯状细胞增生和化生以及粘液过多是慢性气道疾病的突出病理，例如慢性阻塞性肺病（COPD）、囊性纤维化（CF）和慢性支气管炎。呼吸道病原体（包括铜绿假单胞菌）的慢性感染会加剧周期性促炎反应和粘液分泌过多。铜绿假单胞菌及其毒力因子绿脓素通过激活拮抗信号通路 EGFR-AKT/ERK1/2 和 IL-4/IL-13-STAT6-SPDEF 来抑制粘液稳态的关键转录调节因子 FOXA2，从而导致这些病理。然而，之前尚未探索过 FOXA2 靶向治疗。在这里，我们研究了重新利用肠促胰岛素模拟物 Exendin-4 以恢复 FOXA2 介导的气道粘液稳态的可行性。我们发现 Exendin-4 恢复了 FOXA2 表达，减弱了 COPD 和 CF 患病气道细胞中粘蛋白的产生，并减少了小鼠肺中的粘蛋白和铜绿假单胞菌负荷。从机制上讲，Exendin-4 激活了 GLP1R-PKA-PPAR-γ 依赖性磷酸酶 PTEN 和 PTP1B，它们抑制了 EGFR 和 STAT6 信号级联中的关键激酶。我们的结果可能会导致重新利用 Exendin-4 和其他肠促胰岛素模拟物以恢复 FOXA2 功能并最终调节患病气道中过多的粘液。
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