IL-5 signaling in asthmatic derived fibroblasts exacerbates airway remodeling through ECM dysregulation and apoptosis resistance

作者：Rola AbuJabal, Tasneem M. Alanta, Reem Sami Alhamidi, Alaa Muayad Altaie, Lina Sahnoon, Bushra Mdkhana, Bassam Mahboub, Yves Laumonnier, Rifat Hamoudi, Khuloud Bajbouj, Qutayba Hamid · 发表于：Respiratory Research · 年份：2025 · DOI：10.1186/s12931-025-03371-x · 被引用次数：6 · 研究领域：Asthma and respiratory diseases、Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Inhalation and Respiratory Drug Delivery

BACKGROUND: Airway remodelling, a critical feature of severe asthma, involves fibroblast-driven extracellular matrix (ECM) dysregulation. While IL-5 is pivotal in eosinophilic inflammation, its direct role in fibroblast-mediated fibrosis remains undefined. METHODS: Primary lung fibroblasts from asthmatic and healthy donors were stimulated with 0.5 ng/ml of IL-5 for several time points. ECM components, Matrix metalloproteinases (MMPs), Tissue inhibitor of metalloproteinases (TIMPs), and cytokines were analysed via quantitative real time-PCR (qRT-PCR), Western blot, ELISA, and flow cytometry. RNA sequencing and absolute gene set enrichment analysis (absGSEA) identified signaling pathways. Apoptosis was assessed using Annexin V/PI staining. RESULTS: IL-5 shown to markedly increase the expression of ECM proteins, including collagen I and fibronectin, in asthmatic fibroblasts. It also upregulated MMP-2 and MMP-3 expression, alongside increased levels of TIMP-1 and TIMP-2. Moreover, IL-5 promoted the secretion of IL-6 and TGF-β. RNA-seq analysis identified 472 differentially expressed genes in asthmatic fibroblasts, highlighting activation of the MAPK pathway and suppression of apoptosis through NR4A1 upregulation. IL-5 further reduced fibroblast apoptosis and enhanced IL-5Rα expression, indicating potential autocrine signalling. CONCLUSION: IL-5 directly activates lung fibroblasts to drive airway remodelling in severe asthma through ECM deposition, MMP/TIMP imbalance, and pro-fibr...