中性粒细胞外陷阱的产生和CCL4L2的表达对哮喘皮质类固醇反应的影响
2023/06/25
摘要
中性粒细胞外陷阱（NETs）与哮喘患者吸入皮质类固醇（ICS）反应之间的关系尚不清楚。为了更好地理解这种关系，我们在台湾儿童哮喘研究联合会中使用加权基因共表达网络分析和通路富集方法分析了哮喘控制和未控制儿童的血液转录组。我们鉴定了298个未控制的哮喘特异性差异表达基因和一个与中性粒细胞介导的免疫相关的基因模块，强调了中性粒细胞在未控制哮喘中的潜在作用。我们还发现，NET丰度与患者对ICS无反应有关。在中性粒细胞性气道炎症小鼠模型中，类固醇治疗不能抑制中性粒细胞炎症和气道高反应性。然而，脱氧核糖核酸酶I（DNase I）对NET的破坏有效地抑制了气道高反应性和炎症。使用中性粒细胞特异性转录组学图谱，我们发现CCL4L2与ICS在哮喘中的无反应有关，这在人类和小鼠肺组织中得到了验证。CCL4L2的表达也与ICS治疗后的肺功能变化呈负相关。总之，类固醇不能抑制中性粒细胞性气道炎症，这突出了使用替代疗法的潜在需求，如白三烯受体拮抗剂或针对中性粒细胞相关表型的DNase I。此外，这些结果强调CCL4L2是ICS难治性哮喘患者的潜在治疗靶点
Neutrophil extracellular trap production and CCL4L2 expression influence corticosteroid response in asthma
Tsai, C. H., Lai, A. C., Lin, Y. C., Chi, P. Y., Chen, Y. C., Yang, Y. H., Chen, C. H., Shen, S. Y., Hwang, T. L., Su, M. W., Hsu, I. L., Huang, Y. C., Maitland-van der Zee, A. H., McGeachie, M. J., Tantisira, K. G., Chang, Y. J., & Lee, Y. L.
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.
中性粒细胞外陷阱（NETs）与哮喘患者吸入皮质类固醇（ICS）反应之间的关系尚不清楚。为了更好地理解这种关系，我们在台湾儿童哮喘研究联合会中使用加权基因共表达网络分析和通路富集方法分析了哮喘控制和未控制儿童的血液转录组。我们鉴定了298个未控制的哮喘特异性差异表达基因和一个与中性粒细胞介导的免疫相关的基因模块，强调了中性粒细胞在未控制哮喘中的潜在作用。我们还发现，NET丰度与患者对ICS无反应有关。在中性粒细胞性气道炎症小鼠模型中，类固醇治疗不能抑制中性粒细胞炎症和气道高反应性。然而，脱氧核糖核酸酶I（DNase I）对NET的破坏有效地抑制了气道高反应性和炎症。使用中性粒细胞特异性转录组学图谱，我们发现CCL4L2与ICS在哮喘中的无反应有关，这在人类和小鼠肺组织中得到了验证。CCL4L2的表达也与ICS治疗后的肺功能变化呈负相关。总之，类固醇不能抑制中性粒细胞性气道炎症，这突出了使用替代疗法的潜在需求，如白三烯受体拮抗剂或针对中性粒细胞相关表型的DNase I。此外，这些结果强调CCL4L2是ICS难治性哮喘患者的潜在治疗靶点
(中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校)
(Sci Transl Med. 2023 Jun 7; DOI: 0.1126/scitranslmed.adf3843)
(Sci Transl Med. 2023 Jun 7; DOI: 0.1126/scitranslmed.adf3843)
Neutrophil extracellular trap production and CCL4L2 expression influence corticosteroid response in asthma
Tsai, C. H., Lai, A. C., Lin, Y. C., Chi, P. Y., Chen, Y. C., Yang, Y. H., Chen, C. H., Shen, S. Y., Hwang, T. L., Su, M. W., Hsu, I. L., Huang, Y. C., Maitland-van der Zee, A. H., McGeachie, M. J., Tantisira, K. G., Chang, Y. J., & Lee, Y. L.
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.
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