1. A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma.
- Author
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Everman JL, Sajuthi SP, Liegeois MA, Jackson ND, Collet EH, Peters MC, Chioccioli M, Moore CM, Patel BB, Dyjack N, Powell R, Rios C, Montgomery MT, Eng C, Elhawary JR, Mak ACY, Hu D, Huntsman S, Salazar S, Feriani L, Fairbanks-Mahnke A, Zinnen GL, Michel CR, Gomez J, Zhang X, Medina V, Chu HW, Cicuta P, Gordon ED, Zeitlin P, Ortega VE, Reisdorph N, Dunican EM, Tang M, Elicker BM, Henry TS, Bleecker ER, Castro M, Erzurum SC, Israel E, Levy BD, Mauger DT, Meyers DA, Sumino K, Gierada DS, Hastie AT, Moore WC, Denlinger LC, Jarjour NN, Schiebler ML, Wenzel SE, Woodruff PG, Rodriguez-Santana J, Pearson CG, Burchard EG, Fahy JV, and Seibold MA
- Subjects
- Child, Humans, Cytokines, Epithelial Cells metabolism, Nasal Mucosa metabolism, Polymorphism, Genetic, Respiratory Mucosa metabolism, Asthma genetics, Asthma metabolism, GPI-Linked Proteins genetics, GPI-Linked Proteins metabolism, Interleukin-13 genetics, Interleukin-13 metabolism, Lectins genetics, Lectins metabolism, Mucin 5AC genetics, Mucin 5AC metabolism, Mucus metabolism
- Abstract
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 both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma., (© 2024. The Author(s).)- Published
- 2024
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