Translational Inflammation Research Division & Core Facility for Single Cell Multiomics, Member of the German Center for Lung Research (DZL) and the Universities of Giessen and Marburg Lung Center (UGMLC), Medical Faculty, Philipps University of Marburg, Marburg, Germany.
Department of Medicine, Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Allergy. 2023 Nov;78(11):2944-2958. doi: 10.1111/all.15824. Epub 2023 Jul 24.
Plasma extracellular vesicles (EVs) represent a vital source of molecular information about health and disease states. Due to their heterogenous cellular sources, EVs and their cargo may predict specific pathomechanisms behind disease phenotypes. Here we aimed to utilize EV microRNA (miRNA) signatures to gain new insights into underlying molecular mechanisms of obesity-associated low type-2 asthma.
Obese low type-2 asthma (OA) and non-obese low type-2 asthma (NOA) patients were selected from an asthma cohort conjointly with healthy controls. Plasma EVs were isolated and characterised by nanoparticle tracking analysis. EV-associated small RNAs were extracted, sequenced and bioinformatically analysed.
Based on EV miRNA expression profiles, a clear distinction between the three study groups could be established using a principal component analysis. Integrative pathway analysis of potential target genes of the differentially expressed miRNAs revealed inflammatory cytokines (e.g., interleukin-6, transforming growth factor-beta, interferons) and metabolic factors (e.g., insulin, leptin) signalling pathways to be specifically associated with OA. The miR-17-92 and miR-106a-363 clusters were significantly enriched only in OA. These miRNA clusters exhibited discrete bivariate correlations with several key laboratory (e.g., C-reactive protein) and lung function parameters. Plasma EV miRNA signatures mirrored blood-derived CD4 T-cell transcriptome data, but achieved an even higher sensitivity in identifying specifically affected biological pathways.
The identified plasma EV miRNA signatures and particularly the miR-17-92 and -106a-363 clusters were capable to disentangle specific mechanisms of the obesity-associated low type-2 asthma phenotype, which may serve as basis for stratified treatment development.
血浆细胞外囊泡（EVs）是关于健康和疾病状态的分子信息的重要来源。由于其异质的细胞来源，EVs 及其货物可能预测疾病表型背后的特定病理机制。在这里，我们旨在利用 EV 微小 RNA（miRNA）特征来深入了解肥胖相关的 2 型低哮喘的潜在分子机制。
从哮喘队列中选择肥胖的 2 型低哮喘（OA）和非肥胖的 2 型低哮喘（NOA）患者，同时选择健康对照组。通过纳米颗粒跟踪分析分离和表征血浆 EVs。提取、测序和生物信息学分析 EV 相关的小 RNA。
基于 EV miRNA 表达谱，使用主成分分析可以清楚地区分三组研究人群。差异表达 miRNA 的潜在靶基因的综合途径分析表明，炎症细胞因子（如白细胞介素 6、转化生长因子-β、干扰素）和代谢因子（如胰岛素、瘦素）信号通路与 OA 特异性相关。miR-17-92 和 miR-106a-363 簇仅在 OA 中显著富集。这些 miRNA 簇与几个关键的实验室（如 C 反应蛋白）和肺功能参数存在离散的双变量相关性。血浆 EV miRNA 特征反映了血液来源的 CD4 T 细胞转录组数据，但在识别特定受影响的生物学途径方面具有更高的灵敏度。
所鉴定的血浆 EV miRNA 特征，特别是 miR-17-92 和 -106a-363 簇，能够分解肥胖相关的 2 型低哮喘表型的特定机制，这可能为分层治疗的发展提供依据。
