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Increased intracellular Cl - concentration promotes ongoing inflammation in airway epithelium.
- Source :
-
Mucosal immunology [Mucosal Immunol] 2018 Jul; Vol. 11 (4), pp. 1149-1157. Date of Electronic Publication: 2018 Mar 15. - Publication Year :
- 2018
-
Abstract
- Airway epithelial cells harbor the capacity of active Cl <superscript>-</superscript> transepithelial transport and play critical roles in modulating innate immunity. However, whether intracellular Cl <superscript>-</superscript> accumulation contributes to relentless airway inflammation remains largely unclear. This study showed that, in airway epithelial cells, intracellular Cl <superscript>-</superscript> concentration ([Cl <superscript>-</superscript> ] <subscript>i</subscript> ) was increased after Pseudomonas aeruginosa lipopolysaccharide (LPS) stimulation via nuclear factor-κB (NF-κB)-phosphodiesterase 4D (PDE4D)-cAMP signaling pathways. Clamping [Cl <superscript>-</superscript> ] <subscript>i</subscript> 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 <superscript>-</superscript> -SGK1 signaling pathway was pronouncedly activated in patients with bronchiectasis, a chronic airway inflammatory disease. Conversely, hydrogen sulfide (H <subscript>2</subscript> S), a sulfhydryl-containing gasotransmitter, confers anti-inflammatory effects through decreasing [Cl <superscript>-</superscript> ] <subscript>i</subscript> via activation of cystic fibrosis transmembrane conductance regulator (CFTR). Our study confirms that intracellular Cl <superscript>-</superscript> is a crucial mediator of sustained airway inflammation. Medications that abrogate excessively increased intracellular Cl <superscript>-</superscript> may offer novel targets for the management of airway inflammatory diseases.
- Subjects :
- Adult
Animals
Cell Line
Female
Humans
Immediate-Early Proteins metabolism
Immunity, Innate
Lipopolysaccharides immunology
Male
Mice
Mice, Inbred Strains
Middle Aged
NF-kappa B metabolism
Protein Serine-Threonine Kinases metabolism
Respiratory Mucosa pathology
Signal Transduction
Bronchiectasis immunology
Chlorides metabolism
Inflammation immunology
Intracellular Space metabolism
Pseudomonas aeruginosa immunology
Respiratory Mucosa immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1935-3456
- Volume :
- 11
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Mucosal immunology
- Publication Type :
- Academic Journal
- Accession number :
- 29545647
- Full Text :
- https://doi.org/10.1038/s41385-018-0013-8