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 and Max A. Seibold ()
Additional contact information
Jamie L. Everman: National Jewish Health
Satria P. Sajuthi: National Jewish Health
Maude A. Liegeois: University of California-San Francisco
Nathan D. Jackson: National Jewish Health
Erik H. Collet: University of Colorado—Anschutz Medical Campus
Michael C. Peters: University of California–San Francisco
Maurizio Chioccioli: Yale University School of Medicine
Camille M. Moore: National Jewish Health
Bhavika B. Patel: National Jewish Health
Nathan Dyjack: National Jewish Health
Roger Powell: University of Colorado—Anschutz Medical Campus
Cydney Rios: National Jewish Health
Michael T. Montgomery: National Jewish Health
Celeste Eng: University of California-San Francisco
Jennifer R. Elhawary: University of California-San Francisco
Angel C. Y. Mak: University of California-San Francisco
Donglei Hu: University of California-San Francisco
Scott Huntsman: University of California-San Francisco
Sandra Salazar: University of California-San Francisco
Luigi Feriani: University of Cambridge
Ana Fairbanks-Mahnke: National Jewish Health
Gianna L. Zinnen: National Jewish Health
Cole R. Michel: University of Colorado—Anschutz Medical Campus
Joe Gomez: University of Colorado—Anschutz Medical Campus
Xing Zhang: University of Colorado—Anschutz Medical Campus
Vivian Medina: Centro de Neumología Pediatrica
Hong Wei Chu: National Jewish Health
Pietro Cicuta: University of Cambridge
Erin D. Gordon: University of California–San Francisco
Pamela Zeitlin: National Jewish Health
Victor E. Ortega: Mayo Clinic
Nichole Reisdorph: University of Colorado—Anschutz Medical Campus
Eleanor M. Dunican: St. Vincent’s University Hospital, University College Dublin
Monica Tang: University of California–San Francisco
Brett M. Elicker: University of California-San Francisco
Travis S. Henry: Duke University
Eugene R. Bleecker: 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: Mayo Clinic
Kaharu Sumino: Washington University School of Medicine
David S. Gierada: Washington University
Annette T. Hastie: Allergy and Immunologic Diseases
Wendy C. Moore: 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: University of California–San Francisco
Jose Rodriguez-Santana: Centro de Neumología Pediatrica
Chad G. Pearson: University of Colorado—Anschutz Medical Campus
Esteban G. Burchard: University of California-San Francisco
John V. Fahy: University of California-San Francisco
Max A. Seibold: National Jewish Health

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-48034-5

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