Nature Communications (May 2024)
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,
- 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,
- Sally E. Wenzel,
- Prescott G. Woodruff,
- Jose Rodriguez-Santana,
- Chad G. Pearson,
- Esteban G. Burchard,
- John V. Fahy,
- Max A. Seibold
Affiliations
- Jamie L. Everman
- Center for Genes, Environment, and Health, National Jewish Health
- Satria P. Sajuthi
- Center for Genes, Environment, and Health, National Jewish Health
- Maude A. Liegeois
- Department of Medicine, University of California-San Francisco
- Nathan D. Jackson
- Center for Genes, Environment, and Health, National Jewish Health
- Erik H. Collet
- Department of Cell and Developmental Biology, University of Colorado—Anschutz Medical Campus
- Michael C. Peters
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California–San Francisco
- Maurizio Chioccioli
- Department of Genetics and Comparative Medicine, Yale University School of Medicine
- Camille M. Moore
- Center for Genes, Environment, and Health, National Jewish Health
- Bhavika B. Patel
- Center for Genes, Environment, and Health, National Jewish Health
- Nathan Dyjack
- Center for Genes, Environment, and Health, National Jewish Health
- Roger Powell
- Department of Pharmaceutical Sciences, University of Colorado—Anschutz Medical Campus
- Cydney Rios
- Center for Genes, Environment, and Health, National Jewish Health
- Michael T. Montgomery
- Center for Genes, Environment, and Health, National Jewish Health
- Celeste Eng
- Department of Medicine, University of California-San Francisco
- Jennifer R. Elhawary
- Department of Medicine, University of California-San Francisco
- Angel C. Y. Mak
- Department of Medicine, University of California-San Francisco
- Donglei Hu
- Department of Medicine, University of California-San Francisco
- Scott Huntsman
- Department of Medicine, University of California-San Francisco
- Sandra Salazar
- Department of Medicine, University of California-San Francisco
- Luigi Feriani
- Biological and Soft Systems Sector, Cavendish Laboratory, University of Cambridge
- Ana Fairbanks-Mahnke
- Center for Genes, Environment, and Health, National Jewish Health
- Gianna L. Zinnen
- Center for Genes, Environment, and Health, National Jewish Health
- Cole R. Michel
- Department of Pharmaceutical Sciences, University of Colorado—Anschutz Medical Campus
- Joe Gomez
- Department of Pharmaceutical Sciences, University of Colorado—Anschutz Medical Campus
- Xing Zhang
- Department of Pharmaceutical Sciences, University of Colorado—Anschutz Medical Campus
- Vivian Medina
- Centro de Neumología Pediatrica
- Hong Wei Chu
- Department of Medicine, National Jewish Health
- Pietro Cicuta
- Biological and Soft Systems Sector, Cavendish Laboratory, University of Cambridge
- Erin D. Gordon
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California–San Francisco
- Pamela Zeitlin
- Department of Pediatrics, National Jewish Health
- Victor E. Ortega
- Mayo Clinic
- Nichole Reisdorph
- Department of Pharmaceutical Sciences, University of Colorado—Anschutz Medical Campus
- Eleanor M. Dunican
- School of Medicine, St. Vincent’s University Hospital, University College Dublin
- Monica Tang
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California–San Francisco
- Brett M. Elicker
- University of California-San Francisco
- Travis S. Henry
- Duke University
- Eugene R. Bleecker
- Department of Internal Medicine, Mayo Clinic
- Mario Castro
- University of Kansas Medical Center
- Serpil C. Erzurum
- Cleveland Clinic
- Elliot Israel
- Harvard University
- Bruce D. Levy
- Brigham and Women’s Hospital and Harvard University
- David T. Mauger
- Pennsylvania State University
- Deborah A. Meyers
- Department of Internal Medicine, Mayo Clinic
- Kaharu Sumino
- Department of Medicine, Washington University School of Medicine
- David S. Gierada
- Washington University
- Annette T. Hastie
- Wake Forest University School of Medicine, Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases
- Wendy C. Moore
- Wake Forest University School of Medicine, Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases
- Loren C. Denlinger
- University of Wisconsin-Madison
- Nizar N. Jarjour
- University of Wisconsin-Madison
- Mark L. Schiebler
- University of Wisconsin-Madison
- Sally E. Wenzel
- University of Pittsburgh
- Prescott G. Woodruff
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California–San Francisco
- Jose Rodriguez-Santana
- Centro de Neumología Pediatrica
- Chad G. Pearson
- Department of Cell and Developmental Biology, University of Colorado—Anschutz Medical Campus
- Esteban G. Burchard
- Department of Medicine, University of California-San Francisco
- John V. Fahy
- Department of Medicine, University of California-San Francisco
- Max A. Seibold
- Center for Genes, Environment, and Health, National Jewish Health
- DOI
- https://doi.org/10.1038/s41467-024-48034-5
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 17
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.
