Increased intracellular Cl - concentration promotes ongoing inflammation in airway epithelium

• Published in: Mucosal immunology Vol. 11; no. 4; pp. 1149 - 1157
• Main Authors: Zhang, Yi-Lin, Chen, Peng-Xiao, Guan, Wei-Jie, Guo, Hong-Mei, Qiu, Zhuo-Er, Xu, Jia-Wen, Luo, Yu-Li, Lan, Chong-Feng, Xu, Jian-Bang, Hao, Yuan, Tan, Ya-Xia, Ye, Ke-Nan, Lun, Zhao-Rong, Zhao, Lei, Zhu, Yun-Xin, Huang, Jiehong, Ko, Wing-Hung, Zhong, Wei-De, Zhou, Wen-Liang, Zhong, Nan-Shan
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.07.2018
• Subjects: Adult; Animals; Bronchiectasis; Bronchiectasis - immunology; Cell activation; Cell Line; Chlorides - metabolism; Cystic fibrosis; Epithelial cells; Epithelium; Female; Glucocorticoids; Humans; Hydrogen sulfide; Immediate-Early Proteins - metabolism; Immunity, Innate; Inflammation; Inflammation - immunology; Inflammatory diseases; Innate immunity; Intracellular; Intracellular Space - metabolism; Kinases; Lipopolysaccharides; Lipopolysaccharides - immunology; Male; Mice; Mice, Inbred Strains; Middle Aged; NF-kappa B - metabolism; NF-κB protein; Phosphodiesterase; Phosphorylation; Protein kinase; Protein Serine-Threonine Kinases - metabolism; Pseudomonas aeruginosa - immunology; Respiratory Mucosa - immunology; Respiratory Mucosa - pathology; Respiratory tract; Respiratory tract diseases; Signal Transduction
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/s41385-018-0013-8

Airway epithelial cells harbor the capacity of active Cl transepithelial transport and play critical roles in modulating innate immunity. However, whether intracellular Cl accumulation contributes to relentless airway inflammation remains largely unclear. This study showed that, in airway epithelial cells, intracellular Cl concentration ([Cl ] ) was increased after Pseudomonas aeruginosa lipopolysaccharide (LPS) stimulation via nuclear factor-κB (NF-κB)-phosphodiesterase 4D (PDE4D)-cAMP signaling pathways. Clamping [Cl ] at high levels or prolonged treatment with LPS augmented serum- and glucocorticoid-inducible protein kinase 1 (SGK1) phosphorylation and subsequently triggered NF-κB 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 (H S), a sulfhydryl-containing gasotransmitter, confers anti-inflammatory effects through decreasing [Cl ] 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.