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

Author

Listed:
  • 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
    National Jewish Health
    University of Colorado—Anschutz Medical Campus)

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.

Suggested Citation

  • 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 Po, 2024. "A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48034-5
    DOI: 10.1038/s41467-024-48034-5
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    References listed on IDEAS

    as
    1. Satria P. Sajuthi & Jamie L. Everman & Nathan D. Jackson & Benjamin Saef & Cydney L. Rios & Camille M. Moore & Angel C. Y. Mak & Celeste Eng & Ana Fairbanks-Mahnke & Sandra Salazar & Jennifer Elhawary, 2022. "Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Olivier Delaneau & Halit Ongen & Andrew A. Brown & Alexandre Fort & Nikolaos I. Panousis & Emmanouil T. Dermitzakis, 2017. "A complete tool set for molecular QTL discovery and analysis," Nature Communications, Nature, vol. 8(1), pages 1-7, August.
    3. Kyle J. Travaglini & Ahmad N. Nabhan & Lolita Penland & Rahul Sinha & Astrid Gillich & Rene V. Sit & Stephen Chang & Stephanie D. Conley & Yasuo Mori & Jun Seita & Gerald J. Berry & Joseph B. Shrager , 2020. "A molecular cell atlas of the human lung from single-cell RNA sequencing," Nature, Nature, vol. 587(7835), pages 619-625, November.
    4. Satria P. Sajuthi & Jamie L. Everman & Nathan D. Jackson & Benjamin Saef & Cydney L. Rios & Camille M. Moore & Angel C. Y. Mak & Celeste Eng & Ana Fairbanks–Mahnke & Sandra Salazar & Jennifer Elhawary, 2022. "Author Correction: Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
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