A GM-CSF/IL-33 Pathway Facilitates Allergic Airway Responses to Sub-Threshold House Dust Mite Exposure

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...

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Vydáno v:	PloS one Ročník 9; číslo 2; s. e88714
Hlavní autoři:	Llop-Guevara, Alba, Chu, Derek K., Walker, Tina D., Goncharova, Susanna, Fattouh, Ramzi, Silver, Jonathan S., Moore, Cheryl Lynn, Xie, Juliana L., O’Byrne, Paul M., Coyle, Anthony J., Kolbeck, Roland, Humbles, Alison A., Stämpfli, Martin R., Jordana, Manel
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 14.02.2014 Public Library of Science (PLoS)
Témata:	Allergens Allergies Alveolar Epithelial Cells - drug effects Alveolar Epithelial Cells - immunology Alveolar Epithelial Cells - pathology Alveoli Analysis Animals Asthma B cells Biology CD11b antigen Cytokines Dust Epithelial cells Exposure Female Granulocyte-macrophage colony-stimulating factor Granulocyte-Macrophage Colony-Stimulating Factor - metabolism Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology House dust Humans Hypersensitivity Hypersensitivity - immunology Hypersensitivity - parasitology Immunity - drug effects Immunology Inflammation Inflammation - complications Inflammation - immunology Inflammation - pathology Interleukin-1alpha - metabolism Interleukin-33 Interleukins - metabolism Leukocytes (eosinophilic) Ligands Lung - immunology Lung - parasitology Lung - pathology Lungs Lymphocytes T Macrophages, Alveolar - drug effects Macrophages, Alveolar - metabolism Macrophages, Alveolar - pathology Medicine Mice Mice, Inbred BALB C Mites Models, Immunological Mucus Ox40L protein Pathology Pollutants Pollution control Pyroglyphidae - drug effects Pyroglyphidae - immunology Respiratory tract Time Factors
ISSN:	1932-6203, 1932-6203
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Current address: The Hospital for Sick Children (Sick Kids), Toronto, Ontario, Canada Conceived and designed the experiments: ALG DKC RF JSS AAH MRS MJ. Performed the experiments: ALG DKC TDW SG JSS CLM JLX. Analyzed the data: ALG DKC MJ. Contributed reagents/materials/analysis tools: RK AAH. Wrote the paper: ALG MJ. Provided guidance and critical appraisal of the manuscript: PMO AJC AAH MRS MJ. Current address: Rollins School of Public Health, Atlanta, Georgia, United States of America Competing Interests: As requested, note that the authors Dr. Jonathan S. Silver, Roland Kolbeck and Alison A. Humbles are current employees of MedImmune LLC; and Anthony J. Coyle is a current employee of Pfizer. Therefore, the authors state that this does not alter their adherence to all the PLOS ONE policies on sharing data and materials.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0088714