Paul Foster
Director, Professor, School of Biomedical Sciences and Pharmacy, The University of Newcastle, Australia
Title: Role of IL-36 in pathogen induced exacerbation of asthma
Biography
Biography: Paul Foster
Abstract
Asthma is an inflammatory disorder that was once treated as a single disease. Conventional asthma treatment involves the use of inhaled corticosteroids and bronchodilators to inhibit inflammation and airway constriction. However approximately 20% of asthma patients are non-responsive to steroid treatment and have increased risk of hospitalization and death. Respiratory infections are thought to be one of the major risk factors that trigger steroid resistant exacerbations. In these patients innate inflammatory mediators and cells are linked to pathogenesis and disease severity. Our studies investigations have identified novel roles of interleukin (IL)-36 family cytokines in regulating airway inflammation and alterations in lung function during infection and pathogen induced exacerbation of asthma. We found that the expression of IL-36γ was activated by pathogen associated molecular pattern derived from bacteria and viruses in macrophages. Administration of recombinant IL-36γ, in vitro (bronchial epithelial cells) and in vivo (lungs), increased TNF-α, IL-1β, IL-6, IL-33, IL-13, and CXCL1 expression. Interestingly, treatment with IL-36γ also increased recruitment of both type-2 innate lymphoid cells (ILC2) and dendritic cells (DC), both are critical for asthma pathogenesis. We next sought to determine the importance of IL-36γ in asthma using a well characterized murine model of allergic airway disease model. Mice were sensitized and challenged with ovalbumin (OVA) to induce hallmark features of asthma. During allergen challenge, recombinant IL-36γ was administered intranasally. Pulmonary function was then assessed. Mice treated with IL-36γ became insensitive to corticosteroid therapy. In conclusion, we show that infections that trigger asthma exacerbations are linked to IL-36 production and that delivery of this cytokine to the airways results in steroid resistant AHR and neutrophilic inflammation. Our results suggest that IL-36γ could be a potential therapeutics target for neutrophilic and severe asthmatics.