[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Everman, Jamie L ; Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA
Sajuthi, Satria P ; Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA
Liégeois, Maude ; Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) > Biochimie et biologie moléculaire ; Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
Jackson, Nathan D; Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA
Collet, Erik H ; Department of Cell and Developmental Biology, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
Peters, Michael C; Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
Chioccioli, Maurizio; Department of Genetics and Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
Moore, Camille M; Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA
Patel, Bhavika B; Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA
Dyjack, Nathan; Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA
Powell, Roger; Department of Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
Rios, Cydney; Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA
Montgomery, Michael T ; Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA
Eng, Celeste; Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
Elhawary, Jennifer R ; Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
Mak, Angel C Y ; Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
Hu, Donglei ; Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
Huntsman, Scott; Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
Salazar, Sandra; Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
Feriani, Luigi ; Biological and Soft Systems Sector, Cavendish Laboratory, University of Cambridge, Cambridge, UK
Fairbanks-Mahnke, Ana; Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA
Zinnen, Gianna L; Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA
Michel, Cole R; Department of Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
Gomez, Joe; Department of Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
Zhang, Xing; Department of Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
Medina, Vivian; Centro de Neumología Pediatrica, San Juan, PR, USA
Chu, Hong Wei; Department of Medicine, National Jewish Health, Denver, CO, USA
Cicuta, Pietro ; Biological and Soft Systems Sector, Cavendish Laboratory, University of Cambridge, Cambridge, UK
Gordon, Erin D; Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
Zeitlin, Pamela; Department of Pediatrics, National Jewish Health, Denver, CO, USA
Ortega, Victor E; Mayo Clinic, Phoenix, AZ, USA
Reisdorph, Nichole; Department of Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
Dunican, Eleanor M ; School of Medicine, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
Tang, Monica ; Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
Elicker, Brett M; University of California-San Francisco, San Francisco, CA, USA
Henry, Travis S; Duke University, Durham, NC, USA
Bleecker, Eugene R; Department of Internal Medicine, Mayo Clinic, Phoenix, AZ, USA
Castro, Mario ; University of Kansas Medical Center, Kansas City, KS, USA
Erzurum, Serpil C; Cleveland Clinic, Cleveland, OH, USA
Israel, Elliot; Harvard University, Cambridge, MA, USA
Levy, Bruce D; Brigham and Women's Hospital and Harvard University, Cambridge, MA, USA
Mauger, David T; Pennsylvania State University, Hershey, PA, USA
Meyers, Deborah A; Department of Internal Medicine, Mayo Clinic, Phoenix, AZ, USA
Sumino, Kaharu; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Gierada, David S; Washington University, St. Louis, MO, USA
Hastie, Annette T ; Wake Forest University School of Medicine, Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Winston Salem, NC, USA
Moore, Wendy C; Wake Forest University School of Medicine, Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Winston Salem, NC, USA
Denlinger, Loren C; University of Wisconsin-Madison, Madison, WI, USA
Jarjour, Nizar N; University of Wisconsin-Madison, Madison, WI, USA
Schiebler, Mark L ; University of Wisconsin-Madison, Madison, WI, USA
Wenzel, Sally E ; University of Pittsburgh, Pittsburgh, PA, USA
Woodruff, Prescott G; Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
Rodriguez-Santana, Jose; Centro de Neumología Pediatrica, San Juan, PR, USA
Pearson, Chad G ; Department of Cell and Developmental Biology, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
Burchard, Esteban G; Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
Fahy, John V; Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
Seibold, Max A ; Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA. seiboldm@njhealth.org ; Department of Pediatrics, National Jewish Health, Denver, CO, USA. seiboldm@njhealth.org ; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA. seiboldm@njhealth.org
NHLBI - National Heart Lung and Blood Institute NIGMS - National Institute of General Medical Sciences
Funding text :
This work was supported by NIH grants to MAS: R01 HL135156, R01 MD010443, R01 HL128439, P01 HL132821, P01 HL107202, R01 HL117004, DOD Grant W81WH-16-2-0018; by NIH grants to JVF and SARP: HL080414, HL107202, HL109146, and HL146002; by NIH/NCCR grant to NR: S10 OD028538-01A1; and by NIH/NIHGMS grant to C.G.P.: R35 GM140815.
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