IFN-γ and IL-17A drive distinct airway changes in a murine model of steroid-unresponsive severe asthma — ASN Events

IFN-γ and IL-17A drive distinct airway changes in a murine model of steroid-unresponsive severe asthma (#156)

Mahesh Raundhal 1 2 , Christina Morse 2 , Timothy B Oriss 2 , Anupriya Khare 2 , William Horne 3 , Jay Kolls 1 3 , Sally Wenzel 2 , Anuradha Ray 1 2 , Prabir Ray 1 2
  1. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  2. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  3. Richard King Mellon Foundation for Pediatric Research and Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Asthma is an inflammatory disease of the airways characterized by airway obstruction due to inappropriate immune responses against some environmental moieties like house dust mite (HDM) and pollens. Depending on the frequency and intensity of exacerbations experienced, asthma can be categorized as mild-moderate asthma (MMA) that is corticosteroid (CS)- responsive and severe asthma (SA) that is poorly managed by CS. SA constitutes only 5-10% of all asthmatics but accounts for 50% of the healthcare costs and morbidity associated with the disease. The presence of neutrophils in asthma has been correlated with refractoriness to CS, fatal exacerbations and severity. To date, our understanding of the pathological mechanisms central to neutrophil-prominent SA is minimal primarily because of the lack of a suitable animal model, limiting the development and testing of new therapeutics.

Studies in our lab have shown that unlike patients with milder disease, SA patients consistently have a mixed Th1/Th2/Th17 immune phenotype in their airways despite high dose CS treatment. With the association of viral and bacterial infections with severity and frequency of asthma exacerbations, we hypothesized that the combination of an allergen, HDM, with agents that mimic infection would induce a SA phenotype in mice. As in human severe asthmatics, the immune response in this mouse model elicits mixed granulocytic airway inflammation and airway hyperresponsiveness that are poorly responsive to CS. IFN- γ-deficient and IL-17A-deficient mice subjected to the SA model highlight the differential role played by each cytokine in modulating hallmark features of asthma such as airway inflammation, airway hyperreactivity and steroid responsiveness. To identify additional biomarkers for characterization of SA, total lung RNA from mice subjected to the SA model was analyzed by RNA-Seq. Ingenuity Pathway Analysis of the RNA-Seq data revealed potential intermediates (e.g., lipoproteins, proteases, etc) in the IFN- γ and IL-17A signaling pathways that can be targeted for developing novel therapies for SA and potentially other steroid-refractory diseases.