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Publications

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Epublish 4 citations

PubMed: 38724552 DOI: 10.1038/s41467-024-48034-5

A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma.

Nat Commun 15(1):3900

Authors: Jamie L Everman, Satria P Sajuthi, Maude A Liegeois, Nathan D Jackson, Erik H 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 D Gordon, Pamela 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 … and 7 other authors

Affiliations

  • Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA.
  • Department of Medicine, University of California-San Francisco, San Francisco, CA, USA.
  • Department of Cell and Developmental Biology, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA.
  • Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California-San Francisco, San Francisco, CA, USA.
  • Department of Genetics and Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.
  • Department of Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA.
  • Biological and Soft Systems Sector, Cavendish Laboratory, University of Cambridge, Cambridge, UK.
  • Centro de Neumología Pediatrica, San Juan, PR, USA.
  • Department of Medicine, National Jewish Health, Denver, CO, USA.
  • Department of Pediatrics, National Jewish Health, Denver, CO, USA.
  • Mayo Clinic, Phoenix, AZ, USA.
  • School of Medicine, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland.
  • University of California-San Francisco, San Francisco, CA, USA.
  • Duke University, Durham, NC, USA.
  • Department of Internal Medicine, Mayo Clinic, Phoenix, AZ, USA.
  • University of Kansas Medical Center, Kansas City, KS, USA.
  • Cleveland Clinic, Cleveland, OH, USA.
  • Harvard University, Cambridge, MA, USA.
  • Brigham and Women's Hospital and Harvard University, Cambridge, MA, USA.
  • Pennsylvania State University, Hershey, PA, USA.
  • Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Washington University, St. Louis, MO, USA.
  • Wake Forest University School of Medicine, Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Winston Salem, NC, USA.
  • University of Wisconsin-Madison, Madison, WI, USA.

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.

MeSH

Biological Science Disciplines, Epithelial Cells, Genes, Asthma, Gene Expression, Interleukin-13

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