DEL‐1, as an anti‐neutrophil transepithelial migration molecule, inhibits airway neutrophilic inflammation in asthma

Abstract

AbstractBackgroundNeutrophil migration into the airways is a key process in neutrophilic asthma. Developmental endothelial locus‐1 (DEL‐1), an extracellular matrix protein, is a neutrophil adhesion inhibitor that attenuates neutrophilic inflammation.MethodsLevels of DEL‐1 were measured in exhaled breath condensate (EBC) and serum in asthma patients by ELISA. DEL‐1 modulation of neutrophil adhesion and transepithelial migration was examined in a co‐culture model in vitro. The effects of DEL‐1‐adenoviral vector‐mediated overexpression on ovalbumin/lipopolysaccharide (OVA/LPS)‐induced neutrophilic asthma were studied in mice in vivo.ResultsDEL‐1 was primarily expressed in human bronchial epithelial cells and was decreased in asthma patients. Serum DEL‐1 concentrations were reduced in patients with severe asthma compared with normal subjects (567.1 ± 75.3 vs. 276.8 ± 29.36 pg/mL, p < .001) and were negatively correlated to blood neutrophils (r = −0.2881, p = .0384) and neutrophil‐to‐lymphocyte ratio (NLR) (r = −0.5469, p < .0001). DEL‐1 concentrations in the EBC of severe asthmatic patients (113.2 ± 8.09 pg/mL) were also lower than normal subjects (193.0 ± 7.61 pg/mL, p < .001) and were positively correlated with the asthma control test (ACT) score (r = 0.3678, p = .0035) and negatively related to EBC IL‐17 (r = −0.3756, p = .0131), myeloperoxidase (MPO) (r = −0.5967, p = .0055), and neutrophil elastase (NE) (r = −0.5488, p = .0009) expression in asthma patients. Neutrophil adhesion and transepithelial migration in asthma patients were associated with LFA‐1 binding to ICAM‐1 and inhibited by DEL‐1. DEL‐1 mRNA and protein expression in human bronchial epithelial cells were regulated by IL‐17. Exogenous DEL‐1 inhibited IL‐17‐enhanced neutrophil adhesion and migration. DEL‐1 expression was decreased while neutrophil infiltration was increased in the airway of a murine model of neutrophilic asthma. This was prevented by DEL‐1 overexpression.ConclusionsDEL‐1 down‐regulation leads to increased neutrophil migration across bronchial epithelial cells and is associated with neutrophilic airway inflammation in asthma.