Regulatory effects of IL-15 on allergen-induced airway obstruction

• Published in: Journal of allergy and clinical immunology 2018-03, Vol.141 (3), p.906-917.e6
• Main Authors: Venkateshaiah, Sathisha Upparahalli, Zhu, Xiang, Rajavelu, Priya, Niranjan, Rituraj, Manohar, Murli, Verma, Alok K., Lasky, Joseph A., Mishra, Anil
• Format: Article
• Language: English
• Subjects: airway hyperresponsiveness; Airway management; Allergen; Allergens; Allergens - toxicity; Allergies; Animal models; Animals; Aspergillus; Asthma; Asthma - chemically induced; Asthma - genetics; Asthma - immunology; Asthma - pathology; Bronchial Hyperreactivity - chemically induced; Bronchial Hyperreactivity - genetics; Bronchial Hyperreactivity - immunology; Bronchial Hyperreactivity - pathology; CD25 antigen; CD4 antigen; Compliance; Cytokines; Disease Models, Animal; Doxycycline; Enzyme-linked immunosorbent assay; Eosinophils - immunology; Eosinophils - pathology; Exposure; Forkhead protein; Foxp3 protein; Goblet Cells - immunology; Goblet Cells - pathology; Hyperplasia; IL-10; IL-15; Inflammation; Interferon-gamma - genetics; Interleukin 10; Interleukin 13; Interleukin 15; Interleukin 4; Interleukin 5; Interleukin-10 - genetics; Interleukin-10 - immunology; Interleukin-15 - genetics; Interleukin-15 - immunology; Laboratories; Leukocytes (eosinophilic); Lung - immunology; Lung - pathology; Lungs; Lymphocytes; Lymphocytes T; Metastasis; Methacholine; Mice; Mice, Inbred BALB C; Mice, Knockout; Pathogenesis; Preservation; Respiratory tract; Respiratory tract diseases; Uteroglobin - genetics; Uteroglobin - immunology; γ-Interferon
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2017.05.025

Airway obstruction is a physiologic feature of asthma, and IL-15 might have an important role in asthma pathogenesis. We tested the hypothesis that regulation of IL-15 is critical for preservation of allergen-induced airway hyperresponsiveness (AHR), airway resistance, and compliance in response to methacholine. Airway inflammation, AHR, resistance, and compliance were assessed in Il15 gene–deficient mice and IL-15–overexpressing mice in an allergen-induced murine model of asthma. We assessed eosinophil numbers by using anti–major basic protein immunostaining, goblet cell hyperplasia by using periodic acid–Schiff staining, and cytokine and chemokine levels by performing quantitative PCR and ELISA. We made a novel observation that IL-15 deficiency promotes baseline airway resistance in naive mice. Moreover, rIL-15 delivery to the lung downregulates expression of proinflammatory cytokines and improves allergen-induced AHR, airway resistance, and compliance. These observations were further validated in doxycycline-inducible CC10–IL-15 bitransgenic mice. Doxycycline-exposed, Aspergillus species extract–challenged CC10–IL-15 bitransgenic mice exhibited significantly reduced levels of proinflammatory cytokines (IL-4, IL-5, and IL-13) and decreased goblet cell hyperplasia. Airway obstruction, including AHR and airway resistance, was diminished in allergen-challenged doxycycline-exposed compared with non–doxycycline-exposed CC10–IL-15 bitransgenic mice. Mechanistically, we observed that IL-15–mediated protection of airway obstruction is associated with induced IFN-γ– and IL-10–producing regulatory CD4+CD25+ forkhead box p3 (Foxp3)+ T cells. Additionally, we found that a human IL-15 agonist (ALT-803) improved airway resistance and compliance in an experimental asthma model. We report our novel finding that IL-15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens. [Display omitted]