Asthma is a common chronic airway disease. Inhaled corticosteroids (ICS) are the mainstay asthma therapy. However, there is inter-individual variability in the response to ICS, and a few patients have limited disease control and experience persistent symptoms, despite use of ICS. Neutrophil extracellular traps (NETs) have been shown to increase in the lungs and sputum of patients with severe asthma. However, the association between NETs and response to ICS in asthma is unclear.
The research groups led by Dr. Yungling Lee and Dr. Ya-Jen Chang investigate the association between gene, NETs and asthma by the transcriptomic profile from asthma patients, and experimental results from in vitro and asthma murine model. The study unravels that neutrophil-related pathways and a unique neutrophil gene module related to uncontrolled asthma. NETs from peripheral neutrophils were found to be a predictor for ICS non-response. It was confirmed that corticosteroids could not suppress neutrophilic genes or inflammation in both clinical and in vivo settings. Airway hyperreactivity and inflammation were inhibited after disrupting NETs by DNase I treatment in vivo. Finally, from neutrophil RNA sequencing, the gene expression of CCL4L2 was identified to be higher in ICS non-response. CCL4L2 expression showed a significant positive correlation with NET production. These results highlight CCL4L2 and NETs as potential therapeutic targets for individuals with asthma refractory to ICS.
The research team is led by Dr. Yungling Lee and Dr. Ya-Jen Chang in the IBMS, Academia Sinica, and the main work is completed by Dr. Ching-Hui Tsai and Dr. Alan Chuan-Ying Lai. The collaborators consist members from National Taiwan University Hospital, Fu-Jen Catholic University Hospital, MacKay Memorial Hospital, University of Amsterdam, Brigham and Women’s Hospital and Harvard Medical School. The study is funded by Academia Sinica, the National Science and Technology Council and the National Health Research Institutes. The results were published in the Science Translational Medicine on June 7, 2023.