IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma
01 Sep 2013-The Journal of Allergy and Clinical Immunology (Europe PMC Funders)-Vol. 132, Iss: 3, pp 676-685
TL;DR: IL-33 is a relatively steroid-resistant mediator that promotes airway remodeling in patients with STRA and is an important therapeutic target.
Abstract: Background T H 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.
Citations
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TL;DR: A new role for ILCs in the maintenance of metabolic homeostasis has started to emerge, underlining their importance in fundamental physiological processes beyond infection and immunity.
327 citations
Cites background from "IL-33 promotes airway remodeling in..."
...have variously been reported to associate with airway remodeling and viral asthma exacerbation (Gorski et al., 2013; Gregory et al., 2013; Hong et al., 2014; Saglani et al., 2013)....
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...…the actions of the epithelium-derived cytokines IL-25, IL-33, and TSLP, which ptember 18, 2014 ª2014 Elsevier Inc. 367 have variously been reported to associate with airway remodeling and viral asthma exacerbation (Gorski et al., 2013; Gregory et al., 2013; Hong et al., 2014; Saglani et al., 2013)....
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TL;DR: Enhanced neonatal Th2 cell skewing to inhaled allergens results from postnatal hyperactivity of the IL-33 axis during a period of maximal lung remodeling.
255 citations
Cites background from "IL-33 promotes airway remodeling in..."
...Consistently, polymorphisms in IL1RL1, coding for ST2 (IL-33R), as well as the IL33 gene itself have been found associated with asthma and blood eosinophil counts, particularly in childhood asthma (Bønnelykke et al., 2014; Castanhinha et al., 2015; Gordon et al., 2016; Moffatt et al., 2010; Saglani et al., 2013; Savenije et al., 2011; Torgerson et al., 2011; Traister et al., 2015)....
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...The innate type 2 cells all express ST2L (IL-33R) and proliferate in response to IL-33 (Saglani et al., 2013; Schmitz et al., 2005; Willart et al., 2012)....
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...…itself have been found associated with asthma and blood eosinophil counts, particularly in childhood asthma (Bønnelykke et al., 2014; Castanhinha et al., 2015; Gordon et al., 2016; Moffatt et al., 2010; Saglani et al., 2013; Savenije et al., 2011; Torgerson et al., 2011; Traister et al., 2015)....
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...The type 2 response induces goblet cell metaplasia (GCM), airway hyperresponsiveness (AHR), and airway remodeling (Lambrecht and Hammad, 2015; Saglani et al., 2013)....
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TL;DR: Several new classes of asthma drugs—including ultra long acting β agonists and modulators of the interleukin 4 (IL-4), IL-5, IL-13, and IL-17 pathways—have been evaluated in randomized controlled trials, but there is insufficient evidence to make strong recommendations about the use of these newer agents.
Abstract: Asthma affects almost 20 million people in the United States and more than 300 million people worldwide. Of these, 10-15% have severe asthma, which is refractory to commonly available drugs. New drugs are needed because those that are currently available cannot control symptoms and exacerbations in all patients and can cause adverse reactions. In the past 10 years, there have been substantial advances in the understanding of asthma genetics, airway biology, and immune cell signaling. These advances have led to the development of small molecule therapeutics and biologic agents that may improve asthma care in the future. Several new classes of asthma drugs—including ultra long acting β agonists and modulators of the interleukin 4 (IL-4), IL-5, IL-13, and IL-17 pathways—have been evaluated in randomized controlled trials. Other new drug classes—including dissociated corticosteroids, CXC chemokine receptor 2 antagonists, toll-like receptor 9 agonists, and tyrosine kinase inhibitors—remain in earlier phases of development. Despite some preliminary efficacy data, there is insufficient evidence to make strong recommendations about the use of these newer agents. Future research on the clinical efficacy of these biologic agents, the effect of newer agents on severe asthma in pediatric patients, and the biology of non-eosinophilic and corticosteroid resistant asthma is needed to reduce the morbidity of asthma worldwide.
214 citations
TL;DR: Alternaria-specific serine protease activity causes rapid IL-33 release, which underlies the development of a robust TH2 inflammation and exacerbation of allergic airway disease.
Abstract: Background The fungal allergen Alternaria alternata is implicated in severe asthma and rapid onset life-threatening exacerbations of disease. However, the mechanisms that underlie this severe pathogenicity remain unclear. Objective We sought to investigate the mechanism whereby Alternaria was capable of initiating severe, rapid onset allergic inflammation. Methods IL-33 levels were quantified in wild-type and ST2 −/− mice that lacked the IL-33 receptor given inhaled house dust mite, cat dander, or Alternaria , and the effect of inhibiting allergen-specific protease activities on IL-33 levels was assessed. An exacerbation model of allergic airway disease was established whereby mice were sensitized with house dust mite before subsequently being challenged with Alternaria (with or without serine protease activity), and inflammation, remodeling, and lung function assessed 24 hours later. Results Alternaria, but not other common aeroallergens, possessed intrinsic serine protease activity that elicited the rapid release of IL-33 into the airways of mice through a mechanism that was dependent upon the activation of protease activated receptor-2 and adenosine triphosphate signaling. The unique capacity of Alternaria to drive this early IL-33 release resulted in a greater pulmonary inflammation by 24 hours after challenge relative to the common aeroallergen house dust mite. Furthermore, this Alternaria serine protease–IL-33 axis triggered a rapid, augmented inflammation, mucus release, and loss of lung function in our exacerbation model. Conclusion Alternaria- specific serine protease activity causes rapid IL-33 release, which underlies the development of a robust T H 2 inflammation and exacerbation of allergic airway disease.
197 citations
TL;DR: This work reports that the biological activity of IL-33 at its receptor ST2 is rapidly terminated in the extracellular environment by the formation of two disulphide bridges, resulting in an extensive conformational change that disrupts the ST2 binding site.
Abstract: In response to infections and irritants, the respiratory epithelium releases the alarmin interleukin (IL)-33 to elicit a rapid immune response. However, little is known about the regulation of IL-33 following its release. Here we report that the biological activity of IL-33 at its receptor ST2 is rapidly terminated in the extracellular environment by the formation of two disulphide bridges, resulting in an extensive conformational change that disrupts the ST2 binding site. Both reduced (active) and disulphide bonded (inactive) forms of IL-33 can be detected in lung lavage samples from mice challenged with Alternaria extract and in sputum from patients with moderate-severe asthma. We propose that this mechanism for the rapid inactivation of secreted IL-33 constitutes a 'molecular clock' that limits the range and duration of ST2-dependent immunological responses to airway stimuli. Other IL-1 family members are also susceptible to cysteine oxidation changes that could regulate their activity and systemic exposure through a similar mechanism.
192 citations
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TL;DR: A few common alleles are associated with disease risk at all ages and suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation in asthma.
Abstract: A b s t r ac t Background Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease. Methods We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. Results We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P =3×10 −9 ); rs9273349 on chromosome 6, implicating HLA-DQ (P = 7×10 −14 ); rs1342326 on chromosome 9, flanking IL33 (P = 9×10 −10 ); rs744910 on chromosome 15 in SMAD3 (P = 4×10 −9 ); and rs2284033 on chromosome 22 in IL2RB (P = 1.1×10 −8 ). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P = 6×10 −23 ). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma. Conclusions Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)
1,764 citations
"IL-33 promotes airway remodeling in..." refers result in this paper
...This finding is supported by reports of the association between IL-33 levels and childhood asthma in genome-wide association studies.(23) However, unlike IL-13, levels of which peaked at 2 to 3 weeks after allergen exposure in neonatal mice, IL-33 production increased with age and allergen exposure....
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TL;DR: Recent advances in understanding of the sentinel role played by innate immunity provides new targets for disease prevention and treatment that include pathways of innate stimulation by environmental or endogenous pathogen-associated molecular patterns (PAMPs) and danger-associated Molecular patterns (DAMPs), and the identification of new T cell subsets and lymphoid cells.
Abstract: The recognition that asthma is primarily an inflammatory disorder of the airways associated with T helper type 2 (T(H)2) cell-dependent promotion of IgE production and recruitment of mast cells and eosinophils has provided the rationale for disease control using inhaled corticosteroids and other anti-inflammatory drugs. As more has been discovered about the cytokine, chemokine and inflammatory pathways that are associated with T(H)2-driven adaptive immunity, attempts have been made to selectively inhibit these in the hope of discovering new therapeutics as predicted from animal models of allergic inflammation. The limited success of this approach, together with the recognition that asthma is more than allergic inflammation, has drawn attention to the innate immune response in this disease. Recent advances in our understanding of the sentinel role played by innate immunity provides new targets for disease prevention and treatment. These include pathways of innate stimulation by environmental or endogenous pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) to influence the activation and trafficking of DCs, innate sources of cytokines, and the identification of new T cell subsets and lymphoid cells.
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TL;DR: It is shown in a mouse model that influenza infection acutely induced airway hyper-reactivity (AHR), a cardinal feature of asthma, independently of T helper type 2 (TH2) cells and adaptive immunity.
Abstract: Patients with asthma, a major public health problem, are at high risk for serious disease from influenza virus infection, but the pathogenic mechanisms by which influenza A causes airway disease and asthma are not fully known. We show here in a mouse model that influenza infection acutely induced airway hyper-reactivity (AHR), a cardinal feature of asthma, independently of T helper type 2 (T(H)2) cells and adaptive immunity. Instead, influenza infection induced AHR through a previously unknown pathway that required the interleukin 13 (IL-13)-IL-33 axis and cells of the non-T cell, non-B cell innate lymphoid type called 'natural helper cells'. Infection with influenza A virus, which activates the NLRP3 inflammasome, resulted in much more production of IL-33 by alveolar macrophages, which in turn activated natural helper cells producing substantial IL-13.
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