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

doi:10.1016/j.jaci.2013.04.012

Journal of Allergy and Clinical Immunology

Volume 132, Issue 3, September 2013, Pages 676-685.e13

https://doi.org/10.1016/j.jaci.2013.04.012 Get rights and content

Background

T_H2 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.

Section snippets

Animals and reagents

Female BALB/c mice and litters were maintained by in-house breeding in specific pathogen–free conditions and given food and water ad libitum (see the Methods section in this article's Online Repository at www.jacionline.org). Mice were matched for age and background strain. All procedures were conducted in accordance with the Animals (Scientific Procedures) Act 1986. Recombinant mouse IL-33 (50 μg/kg per mouse) for intranasal administration was purchased from eBioscience (Hatfield, United

IL-13 and IL-33 show divergent responses with increasing duration of intranasal HDM exposure in neonatal mice

Because IL-13 has been shown to be necessary and sufficient to induce all features of AAD in adult mice,¹⁸ we investigated the relationship between IL-13 and IL-33 during the development of neonatal AAD (Fig 1, A). The longitudinal production of IL-13 and IL-33 in response to allergen in neonatal mice of increasing age (Fig 1, B and C) was strikingly different. IL-13 production started at week 1, peaked during week 2, and then decreased with increasing age (Fig 1, B). IL-33 production was

Discussion

For the first time, we have shown that IL-33 levels are increased in a neonatal mouse model of HDM-induced AAD and in biopsy specimens from children with STRA. Moreover, IL-33 promotes a specific feature of airway remodeling, increased RBM thickness, through collagen secretion from airway fibroblasts of asthmatic patients in vitro and after direct in vivo administration of IL-33 to mice. Of note, we have shown that AHR and airway remodeling are unaffected when IL-13 is blocked therapeutically

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: S.S. was supported by an Intermediate Clinical Fellowship from the Wellcome Trust, United Kingdom. C.M.L. is a Wellcome Senior Fellow in Basic Biomedical Sciences, and A.B. is a National Institute for Health Research (NIHR) Senior Clinical Investigator. The project was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.

: Disclosure of potential conflict of interest: S. Saglani has received grants from the Wellcome Trust. L. Denney has received grants and travel support from the Wellcome Trust. C. M. Lloyd has received grants from the Wellcome Trust and has consultant arrangements from MedImmune. The rest of the authors declare that they have no relevant conflicts of interest.

View full text

Mechanisms of allergy and clinical immunologyIL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma

Background

Objective

Methods

Results

Conclusion

Section snippets

Animals and reagents

IL-13 and IL-33 show divergent responses with increasing duration of intranasal HDM exposure in neonatal mice

Discussion

Curr Opin Immunol

J Allergy Clin Immunol

Curr Opin Pharmacol

J Allergy Clin Immunol

Chest

Cytokine

Economic burden of impairment in children with severe or difficult-to-treat asthma

Ann Allergy Asthma Immunol

Early thickening of the reticular basement membrane in children with difficult asthma

Am J Respir Crit Care Med

Increased airway smooth muscle mass in children with asthma, cystic fibrosis, and non-cystic fibrosis bronchiectasis

Am J Respir Crit Care Med

Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines

J Allergy Clin Immunol

Dehydroepiandrosterone suppresses eosinophil infiltration and airway hyperresponsiveness via modulation of chemokines and Th2 cytokines in ovalbumin-sensitized mice

J Clin Immunol

Effect of ciclesonide treatment on allergen-induced changes in T cell regulation in asthma

Int Arch Allergy Immunol

Effects of dehydroepiandrosterone on Th2 cytokine production in peripheral blood mononuclear cells from asthmatics

Korean J Intern Med

Lebrikizumab treatment in adults with asthma

N Engl J Med

Nuocytes: expanding the innate cell repertoire in type-2 immunity

J Leukoc Biol

Innate and adaptive immune responses in asthma

Nat Med

Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells

J Immunol

Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity

J Allergy Clin Immunol

Mechanisms of allergy and clinical immunology
IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma