IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma

• Published in: Journal of allergy and clinical immunology 2013-09, Vol.132 (3), p.676-685.e13
• Main Authors: Saglani, Sejal, MD, Lui, Stephen, PhD, Ullmann, Nicola, MD, Campbell, Gaynor A., PhD, Sherburn, Rebekah T., MSc, Mathie, Sara A., MSc, Denney, Laura, PhD, Bossley, Cara J., MD(Res), Oates, Timothy, BSc, Walker, Simone A., BSc, Bush, Andrew, MD, Lloyd, Clare M., PhD
• Format: Article
• Language: English
• Subjects: Adolescent; Age; airway remodeling; Airway Remodeling - physiology; Allergy and Immunology; Animals; Animals, Newborn; Anti-Inflammatory Agents - therapeutic use; Antibiotics; Asthma; Asthma - drug therapy; Asthma - immunology; Asthma - pathology; Biological and medical sciences; Biopsy; Bronchial Hyperreactivity - immunology; Bronchial Hyperreactivity - pathology; Budesonide - therapeutic use; Child; Collagen - immunology; Drug Resistance; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Glucocorticoids - therapeutic use; Humans; IL-33; Immunopathology; Interleukin-13 - immunology; Interleukin-33; Interleukins - administration & dosage; Interleukins - immunology; Laboratories; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Knockout; pediatric; Pyroglyphidae - immunology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Smooth muscle; steroid resistance; Streptococcus infections; therapy
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.04.012

Background TH 2 cytokines are not responsible for the ongoing symptoms and pathology in children with severe therapy-resistant asthma (STRA). IL-33 induces airway hyperresponsiveness, but its role in airway remodeling and steroid resistance is unknown. Objective We sought to investigate the relationship between IL-33 and airway remodeling in pediatric patients with STRA. Methods IL-33 levels were quantified in neonatal mice given inhaled house dust mite (HDM), and the effect of blocking IL-13 on remodeling and IL-33 levels was assessed. HDM-induced allergic airways disease (AAD) in neonatal ST2−/− mice lacking the IL-33 receptor was assessed, together with collagen production after IL-33 administration. The effect of steroid therapy on IL-33 levels in patients with neonatal AAD was explored. IL-33 expression was quantified in endobronchial biopsy (EB) specimens from children with STRA and related to remodeling, and collagen production by airway fibroblasts from pediatric patients stimulated with IL-33 and budesonide was quantified. Results Blocking IL-13 after AAD was established in neonatal mice and did not reduce remodeling or IL-33 levels; airway hyperresponsiveness was only partially reduced. IL-33 promoted collagen synthesis both from asthmatic fibroblasts from pediatric patients and after intranasal administration in mice. Increased cellular expression of IL-33, but not IL-13, was associated with increased reticular basement membrane thickness in EB specimens from children with STRA, whereas remodeling was absent in HDM-exposed ST2−/− mice. IL-33 levels were maintained, whereas IL-13 levels were abrogated by steroid treatment in neonatal HDM-exposed mice and in EB specimens from children with STRA. Conclusion IL-33 is a relatively steroid-resistant mediator that promotes airway remodeling in patients with STRA and is an important therapeutic target.