A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma
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Published:2024-05-09
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Everman Jamie L.ORCID, Sajuthi Satria P.ORCID, Liegeois Maude A.ORCID, Jackson Nathan D., Collet Erik H.ORCID, Peters Michael C., Chioccioli Maurizio, Moore Camille M., Patel Bhavika B., Dyjack Nathan, Powell Roger, Rios Cydney, Montgomery Michael T.ORCID, Eng Celeste, Elhawary Jennifer R.ORCID, Mak Angel C. Y.ORCID, Hu DongleiORCID, Huntsman Scott, Salazar Sandra, Feriani LuigiORCID, Fairbanks-Mahnke Ana, Zinnen Gianna L., Michel Cole R., Gomez Joe, Zhang Xing, Medina Vivian, Chu Hong Wei, Cicuta PietroORCID, Gordon Erin D., Zeitlin Pamela, Ortega Victor E., Reisdorph Nichole, Dunican Eleanor M.ORCID, Tang MonicaORCID, Elicker Brett M., Henry Travis S., Bleecker Eugene R., Castro MarioORCID, Erzurum Serpil C., Israel Elliot, Levy Bruce D., Mauger David T., Meyers Deborah A., Sumino Kaharu, Gierada David S., Hastie Annette T.ORCID, Moore Wendy C., Denlinger Loren C., Jarjour Nizar N., Schiebler Mark L.ORCID, Wenzel Sally E.ORCID, Woodruff Prescott G., Rodriguez-Santana Jose, Pearson Chad G.ORCID, Burchard Esteban G., Fahy John V., Seibold Max A.ORCID
Abstract
AbstractBy 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.
Funder
U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute U.S. Department of Health & Human Services | NIH | NIH Office of the Director U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences
Publisher
Springer Science and Business Media LLC
Reference63 articles.
1. Fahy, J. V. Type 2 inflammation in asthma–present in most, absent in many. Nat. Rev. Immunol. 15, 57–65 (2015). 2. Wesolowska-Andersen, A. & Seibold, M. A. Airway molecular endotypes of asthma: dissecting the heterogeneity. Curr. Opin. Allergy Clin. Immunol. 15, 163–168 (2015). 3. Woodruff, P. G. et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. 180, 388–395 (2009). 4. Sajuthi, S. P. et al. Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium. Nat. Commun. 11, 5139 (2020). 5. Jackson, N. D. et al. Single-cell and population transcriptomics reveal pan-epithelial remodeling in type 2-high asthma. Cell Rep. 32, 107872 (2020).
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