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

• Published in: Allergy (Copenhagen) Vol. 79; no. 5; pp. 1180 - 1194
• Main Authors: Jia, Man, Fu, Heng, Jiang, Xinyu, Wang, Lina, Xu, Jiayan, Barnes, Peter J., Adcock, Ian M., Liu, Yi, He, Shujuan, Zhang, Fan, Yao, Lei, Sun, Peng, Yao, Xin
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.05.2024
• Subjects: adhesion; Animal models; Animals; Asthma; Asthma - immunology; Asthma - metabolism; blood serum; bronchial epithelial cells; Calcium-Binding Proteins - metabolism; Cell Adhesion; Cell Adhesion Molecules - metabolism; Cell culture; coculture; condensates; DEL‐1; Disease Models, Animal; Elastase; Epithelial cells; epithelium; Extracellular matrix; Female; Gene expression; Humans; Inflammation; Inflammation - immunology; Inflammation - metabolism; intercellular adhesion molecule-1; interleukin-17; Leukocyte migration; Leukocytes (neutrophilic); Lipopolysaccharides; Lymphocytes; Matrix protein; Mice; mRNA; myeloperoxidase; neutrophil transepithelial migration; Neutrophils; Neutrophils - immunology; Neutrophils - metabolism; Ovalbumin; Peroxidase; protein synthesis; Respiratory tract diseases; Transendothelial and Transepithelial Migration; asthma; bronchial epithelial cells; DEL‐1; neutrophil transepithelial migration
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/all.15882

Background Neutrophil 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. Methods Levels 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. Results DEL‐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. Conclusions DEL‐1 down‐regulation leads to increased neutrophil migration across bronchial epithelial cells and is associated with neutrophilic airway inflammation in asthma. EBC and serum DEL‐1 levels are decreased in asthma and are correlated with neutrophil related markers. IL‐17 induces downregulation of DEL‐1 in 16HBE, whereas exogenous DEL‐1 significantly suppresses IL‐17‐induced neutrophil adhesion and transepithelial migration in asthma. DEL‐1 overexpression attenuates airway neutrophil infiltration in neutrophilic asthmatic mice.Abbreviations: 16HBE, human bronchial epithelial cell line; AAV, adeno‐associated virus; AHR, airway hyperresponsiveness; DEL‐1, developmental endothelial locus‐1; EBC, exhaled breath condensate; IL‐17, interleukin 17; LPS, lipopolysaccharide; Ly6G, lymphocyte antigen 6 family member G; MPO, myeloperoxidase; NE, neutrophil elastase; NLR, neutrophil‐to‐leukocyte ratio; OVA, ovalbumin; WBC, white blood cells.