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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>IL-5 directly activates lung fibroblasts to drive airway remodelling in severe asthma through ECM deposition, MMP/TIMP imbalance, and pro-fibrotic cytokine secretion, positioning it as a dual mediator of inflammation and fibrosis with novel therapeutic potential.</p> Graphical abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月4日

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  • 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

摘要

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-fibrotic cytokine secretion, positioning it as a dual mediator of inflammation and fibrosis with novel therapeutic potential.

Graphical abstract