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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:144

Article

Allinne, Jeanne¹  Scott, George¹  Lim, Wei Keat¹  Birchard, Dylan¹  Erjefalt, Jonas S.^2,3  Sanden, Caroline³  Ben, Li-Hong¹  Agrawal, Amit¹  Kaur, Navneet¹  Kim, Jee Hae¹  Kamat, Vishal¹  Fury, Wen¹  Huang, Tammy¹  Stahl, Neil¹  Yancopoulos, George D.¹  Murphy, Andrew J.¹  Sleeman, Matthew A.¹  Orengo, Jamie M.¹ 

[1] Regeneron Pharmaceut, Tarrytown, NY USA

[2] Lund Univ, Unit Airway Inflammat, Lund, Sweden

[3] Medetect AB, Lund, Sweden

关键词: IL-33;    airway inflammation;    asthma;    house dust mite;    airway remodeling;    exacerbation;    anti-IL-33;   

DOI  :  10.1016/j.jaci.2019.08.039

来源: Elsevier

【 摘 要 】

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 ST21CD41 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.

【 授权许可】

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