IL-4 levels in sputum correlate with increased mucus production and ciliary dysfunction

Dysfunctional mucociliary clearance is a key feature of several chronic respiratory diseases (Bronchiectasis, COPD, Severe Asthma and CF). IL-4 is a Th2 associated pro-inflammatory cytokine. Anti-IL-4 therapies such as dupilumab are used in severe asthma and in phase 2 trials in COPD. We have recently reported an IL-4 driven endotype in bronchiectasis. The relationships between sputum IL-4, mucus properties (rheology and mass spectrometry) and ciliary function (high speed video microscopy) were investigated. Patients with asthma (n=52), COPD (n=50), CF (n=16), bronchiectasis (n=31) and smokers (n=11) were included. Sputum high in IL-4 had significantly higher Muc5AC (Fig1A) regardless of respiratory condition. IL-4 concentration did not correlate with sputum rheological parameters (Fig1B). Treating differentiated airway epithelial cells in vitro with IL-4 (10ng/ml) for 3 weeks decreased the cilia beat frequency and efficiency whereas the related cytokine IL-13 had no effect (Fig1C&D). Electron microscopy revealed an increase in microvilli associated structures resembling tethered mucins in the IL-4 treated group (Fig1E n=2). Ciliary function was not rescued by tiotropium bromide, a bronchodilator with mucus suppressive properties (Fig1C). High sputum IL-4 in chronic respiratory conditions is associated with increased Muc5AC and impaired ciliary function. Therapies directed against IL-4 may improve mucociliary clearance.