Galectin-9 signaling through TIM-3 is involved in neutrophil-mediated Gram-negative bacterial killing: an effect abrogated within the cystic fibrosis lung.
The T cell Ig and mucin domain-containing molecule (TIM) family of receptors have emerged as potential therapeutic targets to correct abnormal immune function in chronic inflammatory conditions. TIM-3 serves as a functional receptor in structural cells of the airways and via the ligand galectin-9 (Gal-9) can modulate the inflammatory response. The aim of this study was to investigate TIM-3 expression and function in neutrophils, focusing on its potential role in cystic fibrosis (CF) lung disease. Results revealed that TIM-3 mRNA and protein expression values of circulating neutrophils were equal between healthy controls (n = 20) and people with CF (n = 26). TIM-3 was detected on resting neutrophil membranes by FACS analysis, and expression levels significantly increased post IL-8 or TNF-α exposure (p < 0.05). Our data suggest a novel role for TIM-3/Gal-9 signaling involving modulation of cytosolic calcium levels. Via TIM-3 interaction, Gal-9 induced neutrophil degranulation and primed the cell for enhanced NADPH oxidase activity. Killing of Pseudomonas aeruginosa was significantly increased upon bacterial opsonization with Gal-9 (p < 0.05), an effect abrogated by blockade of TIM-3 receptors. This mechanism appeared to be Gram-negative bacteria specific and mediated via Gal-9/ LPS binding. Additionally, we have demonstrated that neutrophil TIM-3/Gal-9 signaling is perturbed in the CF airways due to proteolytic degradation of the receptor. In conclusion, results suggest a novel neutrophil defect potentially contributing to the defective bacterial clearance observed in the CF airways and suggest that manipulation of the TIM-3 signaling pathway may be of therapeutic value in CF, preferably in conjunction with antiprotease treatment.
Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland;
Isabel
I
Vega-Carrascal
David A
DA
Bergin
Oliver J
OJ
McElvaney
Cormac
C
McCarthy
Nessa
N
Banville
Kerstin
K
Pohl
Mitsuomi
M
Hirashima
Vijay K
VK
Kuchroo
Emer P
EP
Reeves
Noel G
NG
McElvaney
D003550:Cystic Fibrosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D005260:Female; D037161:Galectins / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105032:LGALS9 protein, human; D008070:Lipopolysaccharides; D008565:Membrane Proteins