Neutrophil extracellular trap production and CCL4L2 expression influence corticosteroid response in asthma

Ching Hui Tsai, Alan Chuan Ying Lai, Yu Cheng Lin, Po Yu Chi, Yun Chi Chen, Yao Hsu Yang, Chien Han Chen, Sheng Yeh Shen, Tsong Long Hwang, Ming Wei Su, I. Ling Hsu, Yu Chi Huang, Anke H. Maitland-Van der Zee, Michael J. McGeachie, Kelan G. Tantisira, Ya Jen Chang*, Yungling L. Lee*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The association between neutrophil extracellular traps (NETs) and response to inhaled corticosteroids (ICS) in asthma is unclear. To better understand this relationship, we analyzed the blood transcriptomes from children with controlled and uncontrolled asthma in the Taiwanese Consortium of Childhood Asthma Study using weighted gene coexpression network analysis and pathway enrichment methods. We identified 298 uncontrolled asthma-specific differentially expressed genes and one gene module associated with neutrophil-mediated immunity, highlighting a potential role for neutrophils in uncontrolled asthma. We also found that NET abundance was associated with nonresponse to ICS in patients. In a neutrophilic airway inflammation murine model, steroid treatment could not suppress neutrophilic inflammation and airway hyperreactivity. However, NET disruption with deoxyribonuclease I (DNase I) efficiently inhibited airway hyperreactivity and inflammation. Using neutrophil-specific transcriptomic profiles, we found that CCL4L2 was associated with ICS nonresponse in asthma, which was validated in human and murine lung tissue. CCL4L2 expression was also negatively correlated with pulmonary function change after ICS treatment. In summary, steroids fail to suppress neutrophilic airway inflammation, highlighting the potential need to use alternative therapies such as leukotriene receptor antagonists or DNase I that target the neutrophil-associated phenotype. Furthermore, these results highlight CCL4L2 as a potential therapeutic target for individuals with asthma refractory to ICS.

Original languageEnglish
Article numbereadf3843
JournalScience Translational Medicine
Volume15
Issue number699
DOIs
StatePublished - 2023

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