Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Eur Respir J. 2021 Oct 14;58(4). doi: 10.1183/13993003.03312-2020. Print 2021 Oct.
Interleukin (IL)-6 trans-signalling (IL-6TS) is emerging as a pathogenic mechanism in chronic respiratory diseases; however, the drivers of IL-6TS in the airways and the phenotypic characteristic of patients with increased IL-6TS pathway activation remain poorly understood.
Our aim was to identify and characterise COPD patients with increased airway IL-6TS and to elucidate the biological drivers of IL-6TS pathway activation.
We used an IL-6TS-specific sputum biomarker profile (soluble IL-6 receptor (sIL-6R), IL-6, IL-1β, IL-8, macrophage inflammatory protein-1β) to stratify sputum data from patients with COPD (n=74; Biomarkers to Target Antibiotic and Systemic Corticosteroid Therapy in COPD Exacerbation (BEAT-COPD)) by hierarchical clustering. The IL-6TS signature was related to clinical characteristics and sputum microbiome profiles. The induction of neutrophil extracellular trap formation (NETosis) and IL-6TS by were studied in human neutrophils.
Hierarchical clustering revealed an IL-6TS-high subset (n=24) of COPD patients, who shared phenotypic traits with an IL-6TS-high subset previously identified in asthma. The subset was characterised by increased sputum cell counts (p=0.0001), persistent sputum neutrophilia (p=0.0004), reduced quality of life (Chronic Respiratory Questionnaire total score; p=0.008), and increased levels of pro-inflammatory mediators and matrix metalloproteinases in sputum. IL-6TS-high COPD patients showed an increase in Proteobacteria, with as the dominating genus. NETosis induced by was identified as a potential mechanism for increased sIL-6R levels. This was supported by a significant positive correlation between sIL-6R and NETosis markers in bronchoalveolar lavage fluid from COPD patients.
IL-6TS pathway activation due to chronic colonisation with may be an important disease driver in a subset of COPD patients.
白细胞介素 (IL)-6 转导信号 (IL-6TS) 作为慢性呼吸道疾病的致病机制正在显现；然而，气道中 IL-6TS 的驱动因素以及 IL-6TS 通路激活患者的表型特征仍知之甚少。
我们的目的是鉴定和描述气道中 IL-6TS 增加的 COPD 患者，并阐明 IL-6TS 通路激活的生物学驱动因素。
我们使用 IL-6TS 特异性痰生物标志物谱（可溶性 IL-6 受体 (sIL-6R)、IL-6、IL-1β、IL-8、巨噬细胞炎症蛋白-1β）对 COPD 患者（n=74；生物标志物靶向抗生素和全身皮质类固醇治疗 COPD 加重（BEAT-COPD））的痰数据进行分层聚类。IL-6TS 特征与临床特征和痰微生物组谱相关。研究了 对人中性粒细胞形成中性粒细胞细胞外陷阱（NETosis）和 IL-6TS 的诱导作用。
层次聚类显示 COPD 患者中有一个 IL-6TS 高亚组（n=24），该亚组与先前在哮喘中鉴定的 IL-6TS 高亚组具有相似的表型特征。该亚组的特征是痰细胞计数增加（p=0.0001）、持续性痰中性粒细胞增多（p=0.0004）、生活质量下降（慢性呼吸系统问卷总分；p=0.008）以及痰中促炎介质和基质金属蛋白酶水平升高。IL-6TS 高 COPD 患者显示变形菌增加，其中 是主要属。通过 诱导的 NETosis 被确定为增加 sIL-6R 水平的潜在机制。这得到了 COPD 患者支气管肺泡灌洗液中 sIL-6R 与 NETosis 标志物之间存在显著正相关的支持。
由于慢性定植 引起的 IL-6TS 通路激活可能是 COPD 患者亚组中的一个重要疾病驱动因素。
