IL-33 blockade affects mediators of persistence and exacerbation in a model of chronic airway inflammation

Research output: Contribution to journalArticle


Background: Severe inflammatory airway diseases are associated with inflammation that does not resolve, leading to structural changes and an overall environment primed for exacerbations. Objective: We sought to identify and inhibit pathways that perpetuate this heightened inflammatory state because this could lead to therapies that allow for a more quiescent lung that is less predisposed to symptoms and exacerbations. Methods: Using prolonged exposure to house dust mite in mice, we developed a mouse model of persistent and exacerbating airway disease characterized by a mixed inflammatory phenotype. Results: We show that lung IL-33 drives inflammation and remodeling beyond the type 2 response classically associated with IL-33 signaling. IL-33 blockade with an IL-33 neutralizing antibody normalized established inflammation and improved remodeling of both the lung epithelium and lung parenchyma. Specifically, IL-33 blockade normalized persisting and exacerbating inflammatory end points, including eosinophilic, neutrophilic, and ST2+CD4+ T-cell infiltration. Importantly, we identified a key role for IL-33 in driving lung remodeling because anti–IL-33 also re-established the presence of ciliated cells over mucus-producing cells and decreased myofibroblast numbers, even in the context of continuous allergen exposure, resulting in improved lung function. Conclusion: Overall, this study shows that increased IL-33 levels drive a self-perpetuating amplification loop that maintains the lung in a state of lasting inflammation and remodeled tissue primed for exacerbations. Thus IL-33 blockade might ameliorate symptoms and prevent exacerbations by quelling persistent inflammation and airway remodeling.


  • Jeanne Allinne
  • George Scott
  • Wei Keat Lim
  • Dylan Birchard
  • Jonas S. Erjefält
  • Caroline Sandén
  • Li Hong Ben
  • Amit Agrawal
  • Navneet Kaur
  • Jee Hae Kim
  • Vishal Kamat
  • Wen Fury
  • Tammy Huang
  • Neil Stahl
  • George D. Yancopoulos
  • Andrew J. Murphy
  • Matthew A. Sleeman
  • Jamie M. Orengo
External organisations
  • Regeneron Pharmaceuticals, Inc.
  • Medetect AB
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Respiratory Medicine and Allergy


  • airway inflammation, airway remodeling, anti–IL-33, asthma, exacerbation, house dust mite, IL-33
Original languageEnglish
Pages (from-to)1624-1637
Number of pages24
JournalJournal of Allergy and Clinical Immunology
Issue number6
Early online date2019 Sep 25
Publication statusPublished - 2019 Dec
Publication categoryResearch