Increased intracellular Cl^- concentration promotes ongoing inflammation in airway epithelium

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^-]_i) was increased after Pseudomonas aeruginosa lipopolysaccharide (LPS) stimulation via nuclear factor-κB (NF-κB)-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-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 (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.