IL-13 mediated neutrophilic airway inflammation and hyperresponsiveness is corticosteroid-resistant

Background: effective treatment for severe corticosteroid refractory asthma is a significant unmet clinical need. It affects only a small percent of the asthmatic population but accounts for a disproportionate use of healthcare resources. Recent understanding of asthma heterogeneity has evolved beyond clinical characteristics, allowing definition of distinct disease phenotypes such as those defined by levels of Type 2 inflammation (Type-2 high ‘eosinophilic’ disease and Type-2 low ‘neutrophilic’ disease). A recent study using dupilumab (an antibody that blocks the common IL-4 and IL-13 receptor chain, IL-4Rα) as an add-on therapy in adults with uncontrolled persistent asthma showed efficacy irrespective of baseline eosinophil count. It suggests by blocking the receptor, dupilumab may block IL-4/IL- 13 responses not blocked downstream by corticosteroids. The aim of this work was to use a previously described IL-13 transgenic mouse to test the hypothesis that a subset of IL-13 mediated airway responses are corticosteroid-unresponsive and contribute to ongoing airways symptoms.Method: lung specific IL-13 expression was induced using Doxycycline (DOX) in Ccsp-rtTA/Otet-Il- 13 double-transgenic (Ccsp/Il-13) mice. Littermate control mice also received DOX. Where indicated, mice received intra-peritoneal injections of 3mg/kg Dexamethasone for 3-7 days and control mice sham-treated with saline. Lung function to methacholine challenge was performed and lungs harvested for mRNA analysis and immunohistochemistry (IHC). BALF was obtained for ELISA and differential cell counts.Results: as before, Ccsp/Il-13 mice showed significant increase in bronchial hyperresponsiveness (BHR) to methacholine as well as increased bronchial smooth muscle and goblet cell metaplasia. Whilst BALF contained mixed eosinophilic and neutrophilic inflammation, neutrophils predominated. Characteristic Th2-responsive genes as well as genes characteristic of Th17 responses were elevated. Dexamethasone treatment reduced eosinophilia and the associated ‘Th2’ gene signature, but BHR, neutrophil numbers and the ‘Th17’ gene signature remained elevated.Conclusions: although IL-13 promotes eosinophilic airways disease, it can also drive corticosteroid refractory characterized by persistent neutrophilia, Th17 cytokines and maintenance of BHR. The Ccsp/Il-13 mouse may be a useful model for dissecting the molecular pathways and mechanisms associated with predominant neutrophilic, corticosteroid refractory airway disease.