Dysregulation of TIM-3-galectin-9 pathway in the cystic fibrosis airways.
The T-cell Ig and mucin domain-containing molecules (TIMs) have emerged as promising therapeutic targets to correct abnormal immune function in several autoimmune and chronic inflammatory conditions. It has been reported that proinflammatory cytokine dysregulation and neutrophil-dominated inflammation are the main causes of morbidity in cystic fibrosis (CF). However, the role of TIM receptors in CF has not been investigated. In this study, we demonstrated that TIM-3 is constitutively overexpressed in the human CF airway, suggesting a link between CF transmembrane conductance regulator (CFTR) function and TIM-3 expression. Blockade of CFTR function with the CFTR inhibitor-172 induced an upregulation of TIM-3 and its ligand galectin-9 in normal bronchial epithelial cells. We also established that TIM-3 serves as a functional receptor in bronchial epithelial cells, and physiologically relevant concentrations of galectin-9 induced TIM-3 phosphorylation, resulting in increased IL-8 production. In addition, we have demonstrated that both TIM-3 and galectin-9 undergo rapid proteolytic degradation in the CF lung, primarily because of neutrophil elastase and proteinase-3 activity. Our results suggest a novel intrinsic defect that may contribute to the neutrophil-dominated immune response in the CF airways.
Respiratory Research Division, Department of Medicine, Education and Research Centre, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
Isabel
I
Vega-Carrascal
Emer P
EP
Reeves
Toshiro
T
Niki
Tomohiro
T
Arikawa
Paul
P
McNally
Shane J
SJ
O'Neill
Mitsuomi
M
Hirashima
Noel G
NG
McElvaney
D000328:Adult; D000368:Aged; D001980:Bronchi / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002461:Cell Line, Transformed; D002648:Child; D003550:Cystic Fibrosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000502:physiology; D005260:Female; D037161:Galectins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology; D055815:Young Adult
C505032:CFTR protein, human; D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105032:LGALS9 protein, human; D008024:Ligands; D008565:Membrane Proteins; D011994:Recombinant Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator