A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma
Jamie L. Everman, Satria P. Sajuthi, Maude A. Liegeois, Nathan D. Jackson, E. Collet, Michael C. Peters, Maurizio Chioccioli, Camille M. Moore, Bhavika B. Patel, Nathan Dyjack, Roger Powell, Cydney Rios, Michael T. Montgomery, Celeste Eng, Jennifer R. Elhawary, Angel C. Y. Mak, Donglei Hu, Scott Huntsman, Sandra Salazar, Luigi Feriani, Ana Fairbanks-Mahnke, Gianna L. Zinnen, Cole R. Michel, Joe Gomez, Xing Zhang, Vivian Medina, Hong Wei Chu, Pietro Cicuta, Erin Gordon, Pamela L. Zeitlin, Victor E. Ortega, Nichole Reisdorph, Eleanor M. Dunican, Monica Tang, Brett M. Elicker, Travis S. Henry, Eugene R. Bleecker, Mario Castro, Serpil C. Erzurum, Elliot Israel, Bruce D. Levy, David T. Mauger, Deborah A. Meyers, Kaharu Sumino, David S. Gierada, Annette T. Hastie, Wendy C. Moore, Loren C. Denlinger, Nizar N. Jarjour, Mark L. Schiebler, Sally E. Wenzel, Prescott G. Woodruff, José Rodríguez‐Santana, Chad G. Pearson, Esteban G. Burchard, John V. Fahy, Max A. Seibold
Abstract
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.