The role of interleukin-4Rα in the induction of glutamic acid decarboxylase in airway epithelium following acute house dust mite exposure

P>Background Asthma is a disease characterized by airway inflammation, remodelling and dysfunction. Airway inflammation contributes to remodelling, a term that is used to describe structural changes including goblet cell metaplasia (GCM), matrix deposition, and smooth muscle hyperplasia/hypertrophy. GCM has been implicated in asthma mortality by contributing to mucus plugs and leading to asphyxiation. In animal models, this process is highly dependent on IL-13. Recently, we have described an IL-13-dependent up-regulation of a GABAergic signalling system in airway epithelium that contributes to GCM. The mechanism by which IL-13 up-regulates GABA signalling in airway epithelium is unknown. Objectives To test the hypothesis that IL-4R alpha signalling is required for allergen induced up-regulation of GABAergic signalling and GCM. Methods BALB/c mice were exposed to an acute house dust mite (HDM) protocol and received vehicle, anti-IL-4R alpha-monoclonal antibody, or control antibody. Outcomes included airway responses to inhaled methacholine (MCh), histology for eosinophilia and GCM, phosphorylated STAT6 levels using immunohistochemistry and immunoblot, and glutamic acid decarboxylase (GAD) 65/67 and GABA(A) beta(2/3) receptor subunit expression using confocal microscopy. Results Acute HDM exposure resulted in increased airway responses to MCh, lung eosinophilia, STAT6 phosphorylation, elevations in GAD65/67 and GABA(A) beta(2/3) receptor expression, and GCM that were inhibited with anti-IL-4R alpha-monoclonal treatment. Control antibody had no effect. Conclusion The IL-4R alpha is required for allergen-induced up-regulation of a GABAergic system in airway epithelium implicated in GCM following acute HDM exposure. Cite this as: J. A. Hirota, A. Budelsky, D. Smith, B. Lipsky, R. Ellis, Y-Y. Xiang, W-Y. Lu and M. D. Inman, Clinical & Experimental Allergy, 2010 (40) 820-830.