IL-33 blockade affects mediators of persistence and exacerbation in a model of chronic airway inflammation
(2019) In Journal of Allergy and Clinical Immunology 144(6). p.1624-1637- Abstract
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.... (More)
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.
(Less)
- author
- organization
- publishing date
- 2019-12
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- airway inflammation, airway remodeling, anti–IL-33, asthma, exacerbation, house dust mite, IL-33
- in
- Journal of Allergy and Clinical Immunology
- volume
- 144
- issue
- 6
- pages
- 24 pages
- publisher
- Elsevier
- external identifiers
-
- scopus:85074442175
- pmid:31562870
- ISSN
- 0091-6749
- DOI
- 10.1016/j.jaci.2019.08.039
- language
- English
- LU publication?
- yes
- id
- 34a61787-87be-4c81-8742-e546b4df2559
- date added to LUP
- 2019-11-22 10:48:55
- date last changed
- 2024-05-16 01:05:52
@article{34a61787-87be-4c81-8742-e546b4df2559,
abstract = {{<p>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<sup>+</sup>CD4<sup>+</sup> 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.</p>}},
author = {{Allinne, Jeanne and Scott, George and Lim, Wei Keat and Birchard, Dylan and Erjefält, Jonas S. and Sandén, Caroline and Ben, Li Hong and Agrawal, Amit and Kaur, Navneet and Kim, Jee Hae and Kamat, Vishal and Fury, Wen and Huang, Tammy and Stahl, Neil and Yancopoulos, George D. and Murphy, Andrew J. and Sleeman, Matthew A. and Orengo, Jamie M.}},
issn = {{0091-6749}},
keywords = {{airway inflammation; airway remodeling; anti–IL-33; asthma; exacerbation; house dust mite; IL-33}},
language = {{eng}},
number = {{6}},
pages = {{1624--1637}},
publisher = {{Elsevier}},
series = {{Journal of Allergy and Clinical Immunology}},
title = {{IL-33 blockade affects mediators of persistence and exacerbation in a model of chronic airway inflammation}},
url = {{http://dx.doi.org/10.1016/j.jaci.2019.08.039}},
doi = {{10.1016/j.jaci.2019.08.039}},
volume = {{144}},
year = {{2019}},
}