title: IL-13 receptor α1 differentially regulates aeroallergen-induced lung responses.
abstract: IL-13 and IL-4 are hallmark cytokines of Th2-associated diseases including asthma. Recent studies revealed that IL-13Rα1 regulates asthma pathogenesis by mediating both IL-4- and IL-13-mediated responses. Nonetheless, the relative contribution of each cytokine in response to aeroallergen challenge and the degree of functional dichotomy between IL-4 and IL-13 in asthma remains unclear. Consistent with prior publications, we demonstrate that IL-13Rα1 regulates aeroallergen-induced airway resistance and mucus production but not IgE and Th2 cytokine production. We demonstrate that aeroallergen-induced eosinophil recruitment and chemokine production were largely dependent on IL-13Rα1 after Aspergillus but not house dust mite (HDM) challenges. Notably, Aspergillus-challenged mice displayed increased IL-13Rα1-dependent accumulation of dendritic cell subsets into lung-draining lymph nodes in comparison with HDM-challenged mice. Comparison of IL-4 and IL-13 levels in the different experimental models revealed increased IL-4/IL-13 ratios after HDM challenge, likely explaining the IL-13Rα1-independent eosinophilia and chemokine production. Consistently, eosinophil adoptive transfer experiments revealed near ablation of lung eosinophilia in response to Aspergillus in Il13ra1(-/-) mice, suggesting that Aspergillus-induced lung eosinophil recruitment is regulated by IL-13-induced chemokine production rather than altered IL-13 signaling in eosinophils. Furthermore, the near complete protection observed in Il13ra1(-/-) mice in response to Aspergillus challenge was dependent on mucosal sensitization, as alum/Aspergillus-sensitized mice that were rechallenged with Aspergillus developed IL-13Rα1-independent eosinophilia although other asthma parameters remained IL-13Rα1 dependent. These results establish that IL-13Rα1 is required for aeroallergen-induced airway resistance and that allergen-induced chemokine production and consequent eosinophilia is dictated by the balance between IL-4 and IL-13 production in situ.
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Rothenberg@cchmc.org
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: Ting
authors.initials: T
authors.lastname: Wen
authors.forename: Dana
authors.initials: D
authors.lastname: Shik
authors.forename: Eric T
authors.initials: ET
authors.lastname: Cole
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Mingler
authors.forename: Ariel
authors.initials: A
authors.lastname: Munitz
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000485:Allergens / Q000008:administration & dosage* / Q000633:toxicity; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009093:Mucus / Q000276:immunology / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D000393:Air Pollutants; D000485:Allergens; D053661:Interleukin-13 Receptor alpha1 Subunit; D016212:Transforming Growth Factor beta