title: A GM-CSF/IL-33 pathway facilitates allergic airway responses to sub-threshold house dust mite exposure.
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.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, Ontario, Canada.
authors.forename: Alba
authors.initials: A
authors.lastname: Llop-Guevara
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, Ontario, Canada.
authors.forename: Derek K
authors.initials: DK
authors.lastname: Chu
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, Ontario, Canada.
authors.forename: Tina D
authors.initials: TD
authors.lastname: Walker
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, Ontario, Canada.
authors.forename: Susanna
authors.initials: S
authors.lastname: Goncharova
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, Ontario, Canada.
authors.forename: Ramzi
authors.initials: R
authors.lastname: Fattouh
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, United States of America.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Silver
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, Ontario, Canada.
authors.forename: Cheryl Lynn
authors.initials: CL
authors.lastname: Moore
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, Ontario, Canada.
authors.forename: Juliana L
authors.initials: JL
authors.lastname: Xie
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Byrne
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, Ontario, Canada ; Pfizer, Cambridge, Massachusetts, United States of America.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, United States of America.
authors.forename: Roland
authors.initials: R
authors.lastname: Kolbeck
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, United States of America.
authors.forename: Alison A
authors.initials: AA
authors.lastname: Humbles
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, Ontario, Canada ; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Stämpfli
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Hamilton, Ontario, Canada.
authors.forename: Manel
authors.initials: M
authors.lastname: Jordana
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D000818:Animals; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology* / Q000469:parasitology*; D007109:Immunity / Q000187:drug effects; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000473:pathology; D053582:Interleukin-1alpha / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D008168:Lung / Q000276:immunology* / Q000469:parasitology* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018448:Models, Immunological; D039981:Pyroglyphidae / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors
chemical_list: C506535:Il33 protein, mouse; D053582:Interleukin-1alpha; D000067596:Interleukin-33; D007378:Interleukins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor