TH2 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.We sought to investigate the relationship between IL-33 and airway remodeling in pediatric patients with STRA.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.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.IL-33 is a relatively steroid-resistant mediator that promotes airway remodeling in patients with STRA and is an important therapeutic target.
The Journal of allergy and clinical immunology
676 - 685.e13
Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; Respiratory Paediatrics, Royal Brompton Hospital, and National Heart & Lung Institute, Imperial College London, London, United Kingdom.
Animals, Mice, Inbred BALB C, Animals, Newborn, Mice, Knockout, Humans, Mice, Pyroglyphidae, Asthma, Bronchial Hyperreactivity, Budesonide, Collagen, Anti-Inflammatory Agents, Interleukins, Interleukin-13, Glucocorticoids, Drug Resistance, Adolescent, Child, Female, Male, Airway Remodeling, Interleukin-33