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

Publication date: Available online 9 June 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Sathisha Upparahalli Venkateshaiah, Xiang Zhu, Priya Rajavelu, Rituraj Niranjan, Murli Manohar, Alok K. Verma, Joseph A. Lasky, Anil Mishra
BackgroundAirway obstruction is a physiologic feature of asthma and IL-15 may have an important role in the pathogenesis of asthma.ObjectiveWe 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.MethodsAirway 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.ResultsHerein, 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.ConclusionWe report our novel finding that IL-15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens.

Teaser

IL-15 deficiency promotes airway obstruction and IL-15 overexpression protects mice from allergen-Induced airway obstruction including AHR , resistance and compliance in an experimental asthma model.


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