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

Man Jia; Heng Fu; Xinyu Jiang; Lina Wang; Jiayan Xu; Peter J Barnes; Ian M Adcock; Yi Liu; Shujuan He; Fan Zhang; Lei Yao; Peng Sun; Xin Yao

doi:10.1111/all.15882

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

Allergy. 2023 Sep 8. doi: 10.1111/all.15882. Online ahead of print.

Authors

Man Jia¹, Heng Fu¹, Xinyu Jiang¹, Lina Wang¹, Jiayan Xu¹, Peter J Barnes², Ian M Adcock², Yi Liu^{3

4}, Shujuan He⁵, Fan Zhang⁵, Lei Yao¹, Peng Sun¹, Xin Yao¹

Affiliations

¹ Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
² Airway Disease Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.
³ Department of Allergy, Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
⁴ Shandong Key Laboratory of Infections Respiratory Disease, Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
⁵ Department of Respiratory Medicine, Nanjing Red Cross Hospital, Nanjing, China.

PMID: 37681299
DOI: 10.1111/all.15882

Abstract

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.

Keywords: DEL-1; asthma; bronchial epithelial cells; neutrophil transepithelial migration.

Abstract

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