期刊
MUCOSAL IMMUNOLOGY
卷 11, 期 4, 页码 1149-1157出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41385-018-0013-8
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资金
- National 973 projects [2009CB522102, 2010CB945401]
- National Natural Science Foundation of China [31271247, 81471445, 81400010, 81571427]
- Changjiang Scholars and Innovative Research Team in University [ITR0961]
- National Key Technology R&D Program of the 12th National Five-year Development Plan [2012BAI05B01]
- National Key Scientific & Technology : Collaborative innovation of Clinical Research for chronic obstructive pulmonary disease and lung cancer [2013BAI09B09]
- Pearl River S&T Nova Program of Guangzhou [201710010097]
- Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme 2017
Airway epithelial cells harbor the capacity of active Cl- ransepithelial transport and play critical roles in modulating innate immunity. However, whether intracellular Cl- ccumulation contributes to relentless airway inflammation remains largely unclear. This study showed that, in airway epithelial cells, intracellular Cl- oncentration ([Cl-](i)) was increased after Pseudomonas aeruginosa lipopolysaccharide (LPS) stimulation via nuclear factor-kappa B (NF-kappa B)-phosphodiesterase 4D (PDE4D)-cAMP signaling pathways. Clamping [Cl-](i) at high levels or prolonged treatment with LPS augmented serum-and glucocorticoid-inducible protein kinase 1 (SGK1) phosphorylation and subsequently triggered NF-kappa B activation in airway epithelial cells, whereas inhibition of SGK1 abrogated airway inflammation in vitro and in vivo. Furthermore, Cl--SGK1 signaling pathway was pronouncedly activated in patients with bronchiectasis, a chronic airway inflammatory disease. Conversely, hydrogen sulfide (H2S), a sulfhydryl-containing gasotransmitter, confers anti-inflammatory effects through decreasing [Cl-](i) via activation of cystic fibrosis transmembrane conductance regulator (CFTR). Our study confirms that intracellular Cl- is a crucial mediator of sustained airway inflammation. Medications that abrogate excessively increased intracellular Cl- may offer novel targets for the management of airway inflammatory diseases.
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