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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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. 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.

Detaljer

Författare
  • 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
Enheter & grupper
Externa organisationer
  • Regeneron Genetics Center LLC
  • Medetect AB
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Lungmedicin och allergi

Nyckelord

Originalspråkengelska
Sidor (från-till)1624-1637
Antal sidor24
TidskriftJournal of Allergy and Clinical Immunology
Volym144
Utgåva nummer6
Tidigt onlinedatum2019 sep 25
StatusPublished - 2019 dec
PublikationskategoriForskning
Peer review utfördJa