Regulatory effects of Interleukin (IL)-15 on allergen-induced airway obstruction

• Published in: Journal of allergy and clinical immunology 2017-06, Vol.141 (3), p.906-917.e6
• Main Authors: Venkateshaiah, Sathisha Upparahalli, PhD, Zhu, Xiang, PhD, Rajavelu, Priya, PhD, Niranjan, Rituraj, PhD, Manohar, Murli, PhD, Verma, Alok K., PhD, Lasky, Joseph A., MD, Mishra, Anil, PhD
• Format: Article
• Language: English
• Subjects: Allergy and Immunology
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2017.05.025

Abstract Background Airway obstruction is a physiologic feature of asthma and IL-15 may have an important role in the pathogenesis of asthma. Objective We tested the hypothesis that regulation of IL-15 is critical for the preservation of allergen-induced airway hyperresponsiveness (AHR), airway resistance and compliance in response to methacholine. Methods Airway inflammation, AHR, resistance and compliance were assessed in IL-15 - gene deficient mice and IL-15 overexpressing mice in an allergen-induced murine model of asthma. We assessed eosinophils by anti-MBP immunostaining, goblet cells hyperplasia by PAS staining, and cytokines and chemokine levels by performing qPCR and ELISA analyses. Results Herein, we made a novel observation that IL-15 deficiency promotes baseline airway resistance in naïve mice. Moreover, rIL-15 delivery to the lung downregulates expression of proinflammatory cytokines, and improves allergen-induced AHR, resistance and compliance. These observations were further validated in DOX-inducible CC-10-IL-15 transgenic mice. DOX exposed Aspergillus extract challenged CC-10-IL-15 bitransgenic mice exhibited significantly reduced levels of proinflammatory cytokines (IL-4, IL-5, IL-13) and decreased goblet cell hyperplasia. Airway obstruction including AHR and resistance was diminished in allergen challenged DOX exposed mice compared to non-DOX exposed CC-10-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+ Foxp3+ T cells. Additionally, we found that a human IL-15 agonist (ALT-803) improved airway resistance and compliance in an experimental asthma model. Conclusion We report our novel finding that IL-15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens.