IL-5 blockade restores the bronchial epithelium and attenuates airway remodelling in severe asthma
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Rationale
Airway remodelling (AR) contributes to airflow limitation and poor symptom control in severe asthma. While anti-IL-5 therapy improves clinical outcomes in severe asthma, the cellular and molecular mechanisms underlying its effects on AR remain incompletely understood.
Objectives.
To determine whether IL-5 blockade directly modulates airway epithelial biology and contributes to attenuation of AR in severe asthma with eosinophilia (SAE).
Methods.
Patients with SAE underwent bronchoscopy before and after 24 weeks of anti-IL-5 therapy. Paired bronchial brushings (n=12) were analysed using single-cell RNA-sequencing. Histological features of AR were assessed in paired bronchial biopsies (n=16). Functional effects of IL-5 were investigated using wound healing assays in differentiated air-liquid interface (ALI) cultures.
Measurements and Main Results.
Anti-IL-5 treatment improved clinical outcomes without altering airway epithelial cellular composition. Differential gene expression was predominantly restricted to bronchial ciliated epithelial cells, which expressed IL5RA . ALI cultures showed IL-5Rα protein. Anti-IL-5 therapy induced a transcriptional signature in ciliated cells that opposed IL-5-responsive genes. Pseudotime analyses demonstrated preserved epithelial differentiation trajectories but altered programmes related to mucus regulation and ion transport. Cell-cell communication analyses revealed decreased T2-inflammatory processes alongside enrichment of epithelial repair and barrier integrity processes after treatment. Functionally, IL-5 directly impaired epithelial wound repair in ALI cultures. Histological assessment demonstrated increased epithelial E-cadherin expression and reduced sub-basement membrane thickness, extracellular matrix deposition and goblet cell hyperplasia in bronchial biopsies.
Conclusions.
IL-5 blockade modulates epithelial biology at transcriptional, functional and structural levels in SAE and is associated with improved epithelial integrity and reduced features of AR.
Impact
Our findings broaden current understanding of interleukin (IL)-5 biology by demonstrating that IL-5 blockade exerts direct effects on the bronchial epithelium in addition to its established effects on eosinophilic inflammation in asthma. Through single-cell analyses of human bronchial samples, complemented by functional and histological validation we provide novel mechanistic insight into how IL-5 blockade influences epithelial repair, barrier integrity and airway remodelling. These findings advance understanding of severe asthma pathogenesis, provide evidence that structural disease is modifiable and may inform future approaches to disease modification.
At a Glance Commentary
Scientific knowledge on the subject
Interleukin-5 (IL-5) is a key driver of eosinophilic inflammation in severe asthma and anti-IL-5 therapies improve clinical outcomes. Emerging evidence suggests that IL-5 blockade may also improve features of airway remodelling. However, the cellular mechanisms underlying airway structural improvements and the effects of IL-5 blockade on airway structural cells remain poorly understood.
What this study adds to the field
Using paired bronchial samples obtained before and after anti-IL5 treatment, we demonstrate that IL-5 blockade directly modulates bronchial epithelial cell biology. We identify ciliated epithelial cells as an IL-5 responsive population and show that anti-IL-5 therapy alters transcriptional programmes in airway epithelium associated with repair, barrier integrity and airway remodelling. IL-5 blockade shifts cell-cell communication away from inflammation pathways towards pathways supporting epithelial repair. Functionally, IL-5 directly impairs wound healing of differentiated airway epithelial cells in vitro and IL-5 blockade enhances epithelial integrity and reduces remodelling-associated structural changes in vivo . Our findings broaden current understanding of IL-5 biology by demonstrating that the effects of IL-5 blockade extend beyond eosinophil suppression to include direct effects on biological pathways in epithelial cells involved in repair, barrier integrity and airway remodelling in severe asthma.
