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PLoS One. 2014 Feb 14;9(2):e88714. doi: 10.1371/journal.pone.0088714. eCollection 2014.

A GM-CSF/IL-33 pathway facilitates allergic airway responses to sub-threshold house dust mite exposure.

Author information

  • 1Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, Ontario, Canada.
  • 2Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, United States of America.
  • 3Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
  • 4Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, Ontario, Canada ; Pfizer, Cambridge, Massachusetts, United States of America.
  • 5Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, Ontario, Canada ; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Abstract

Allergic asthma is a chronic immune-inflammatory disease of the airways. Despite aeroallergen exposure being universal, allergic asthma affects only a fraction of individuals. This is likely related, at least in part, to the extent of allergen exposure. Regarding house dust mite (HDM), we previously identified the threshold required to elicit allergic responses in BALB/c mice. Here, we investigated the impact of an initial immune perturbation on the response to sub-threshold HDM exposure. We show that transient GM-CSF expression in the lung facilitated robust eosinophilic inflammation, long-lasting antigen-specific Th2 responses, mucus production and airway hyperresponsiveness. This was associated with increased IL-33 levels and activated CD11b(+) DCs expressing OX40L. GM-CSF-driven allergic responses were significantly blunted in IL-33-deficient mice. IL-33 was localized on alveolar type II cells and in vitro stimulation of human epithelial cells with GM-CSF enhanced intracellular IL-33 independently of IL-1α. Likewise, GM-CSF administration in vivo resulted in increased levels of IL-33 but not IL-1α. These findings suggest that exposures to environmental agents associated with GM-CSF production, including airway infections and pollutants, may decrease the threshold of allergen responsiveness and, hence, increase the susceptibility to develop allergic asthma through a GM-CSF/IL-33/OX40L pathway.

PMID:
24551140
[PubMed - indexed for MEDLINE]
PMCID:
PMC3925157
Free PMC Article
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