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

Summary: Blocking IL-33 signaling ameliorates inflammation, tissue remodeling and preserves lung function in a model of persistent and exacerbating airway disease. Background: Severe inflammatory airway diseases are associated with inflammation that fails to 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, as this could lead to therapies that allow for a more quiescent lung, less predisposed to symptoms and exacerbations. Methods: Using prolonged exposure to house dust mite (HDM) 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 endpoints, including eosinophilic, neutrophilic and ST2+ CD4+ T cell infiltration. Importantly, we identified a key role for IL-33 in driving lung remodeling, as anti-IL-33 also reestablished the presence of ciliated cells over mucus producing cells and lowered myofibroblast numbers, even in the context of continuous allergen exposure, resulting in improved lung function. Conclusion: Overall, this study shows that elevated IL-33 drives a self-perpetuating amplification loop that retains the lung in a state of lasting inflammation and remodeled tissue, primed for exacerbations. Thus, IL-33 blockade may ameliorate symptoms and prevent exacerbations by quelling persistent inflammation and airway remodeling. Overall design: Using prolonged exposure to house dust mite (HDM) in mice, we developed a mouse model of persistent and exacerbating airway disease characterized by a mixed inflammatory phenotype. HDM4wk: mouse exposed to house dust mite (HDM) for 4 weeks with no antibody treatment. HDM15wk: mouse exposed to house dust mite (HDM) for 15 weeks with no antibody treatment. HDM15wk_Iso: mouse exposed to house dust mite (HDM) for 15 weeks with isotype control treatment. HDM15wk_antiIL33: mouse exposed to house dust mite (HDM) for 15 weeks with anti-IL-33 antibody treatment.