A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma
By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus.  Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children.  Furthermore, we demonstrate that ITLN1 gene expression is significantly reduced and ITLN-1  protein expression is lost through a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies one of the first biomarkers and targetable pathways for the treatment of mucus obstruction in asthma. Overall design: Bronchial cells were dissociated from the bronchial airway brushes from 2 asthmatic children using Bacillus licheniformis cold active protease (10mg/ml), EDTA (0.5mM), and EGTA (0.5mM) at 4°C with vortex mixing, followed by enzyme neutralization with FBS.  Red blood cell lysis was performed and cells were washed twice in 0.04% BSA/PBS prior to targeted capture for scRNA-seq.