TY - JOUR
T1 - Neutrophil extracellular trap production and CCL4L2 expression influence corticosteroid response in asthma
AU - Tsai, Ching-Hui
AU - Lai, Alan Chuan-Ying
AU - Lin, Yu-Cheng
AU - Chi, Po-Yu
AU - Chen, Yun-Chi
AU - Yang, Yao-Hsu
AU - Chen, Chien-Han
AU - Shen, Sheng-Yeh
AU - Hwang, Tsong-Long
AU - Su, Ming-Wei
AU - Hsu, I. Ling
AU - Huang, Yu-Chi
AU - Maitland-van der Zee, Anke H.
AU - McGeachie, Michael J.
AU - Tantisira, Kelan G.
AU - Chang, Ya-Jen
AU - Lee, Yungling L.
N1 - Funding Information:
We thank the clinical assistants and pediatricians who supported the data collection and all of the parents and children who participated in this study. We also thank the NGS High Throughput Genomics Core, Flow Cytometry Core Facility (AS-CFII-111-212), and the Inflammation Core Facility from Academia Sinica for the technical supports. This study was supported by the 2021-22 Postdoctoral Scholars from Academia Sinica (to C.-H.T.); grants MOST-109-2314-B-001-011 and MOST-110-2314-B-001-002-MY3 (to Y.L.L.) as well as MOST-110-2628-B-001-030 and MOST-111-2320-B-001-025-MY3 (to Y.-J.C.) from the Taiwan Ministry of Science and Technology; the Academia Sinica Investigator Award AS-IA-110-L04 (to Y.-J.C.); Academia Sinica Grand Challenge Award AS-GC-110-05 (to Y.-J.C.); grant 107-CGN03 (to Y.-H.Y.) from the National Taiwan University Hospital; grant NHRI-EX107-10606PI (to Y.L.L.) from the National Health Research Institutes; grant AS-TM-108-01-03 (to Y.L.L.) from Academia Sinica; and grants NIH R01 HL162570 and U01 HL65899 (to K.G.T.) as well as R01 HL139634 and R01 HL155742 (to M.J.M.).
Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved.
PY - 2023/6/7
Y1 - 2023/6/7
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85161144405
U2 - 10.1126/scitranslmed.adf3843
DO - 10.1126/scitranslmed.adf3843
M3 - Article
C2 - 37285400
SN - 1946-6234
VL - 15
SP - eadf3843
JO - Science translational medicine
JF - Science translational medicine
IS - 699
M1 - eadf3843
ER -
SDG 3 Good Health and Well-being