Chronic IL-33 expression predisposes to virus-induced asthma exacerbations by increasing type 2 inflammation and dampening antiviral immunity

Werder, Rhiannon B.; Zhang, Vivian; Lynch, Jason P.; Snape, Natale; Upham, John W.; Spann, Kirsten; Phipps, Simon

doi:10.1016/j.jaci.2017.07.051

Cited by 65 publications

(68 citation statements)

References 57 publications

(88 reference statements)

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“…Girkin et al (40) reported that knockdown of IRF7 abolished RVinduced type I IFN responses in the airways in a mouse model. Werder et al (41) reported that anti-IL-33 therapy suppressed type 2 inflammation, boosted antiviral immunity, and decreased viral replication in a mouse model of virus-induced asthma exacerbations. Together, these findings highlight a mutually antagonistic role for IRF7-related antiviral immunity and IL-33-driven type 2 inflammation in driving alternative exacerbation phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Upper Airway Cell Transcriptomics Identify a Major New Immunological Phenotype with Strong Clinical Correlates in Young Children with Acute Wheezing

Khoo

Read

Franks

et al. 2019

The Journal of Immunology

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Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper-airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7 hi versus IRF7 lo molecular phenotypes, the former exhibiting robust upregulation of Th1/type I IFN responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signaling and downregulation of IFN-g. The two phenotypes also produced distinct clinical phenotypes. For IRF7 lo children, symptom duration prior to hospital presentation was more than twice as long from initial symptoms (p = 0.011) and nearly three times as long for cough (p < 0.001), the odds ratio of admission to hospital was increased more than 4-fold (p = 0.018), and time to recurrence was shorter (p = 0.015). In summary, our findings demonstrate that asthma exacerbations in children can be divided into IRF7 hi versus IRF7 lo phenotypes with associated differences in clinical phenotypes.

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Section: Discussionmentioning

confidence: 99%

Upper Airway Cell Transcriptomics Identify a Major New Immunological Phenotype with Strong Clinical Correlates in Young Children with Acute Wheezing

Khoo

Read

Franks

et al. 2019

The Journal of Immunology

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“…Such mechanisms may partly explain why, in the present study, IL‐33 did not directly induce the synthesis of fibronectin by murine fibroblasts in vitro , whereas per‐nasal administration of IL‐33 in vivo did enhance the expression of fibronectin in the murine airways in a manner compatible with that observed in the OVA‐challenged mice. This and other indirect effects of IL‐33 in vivo might result from its actions on cells other than fibroblasts causing the release of additional mediators, including ILC2s, macrophages and mast cells …”

Section: Discussionmentioning

confidence: 99%

The effects of interleukin‐33 on airways collagen deposition and matrix metalloproteinase expression in a murine surrogate of asthma

Zhang

Wang

et al. 2018

Immunology

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It has been suggested that interleukin-33 (IL-33) plays an important role in the pathogenesis of asthma through a variety of pathways, but its role in airways fibrosis in asthma has not been fully elucidated. In the present study we evaluated changes in the expression of extracellular matrix proteins (ECMs) as well as matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in an IL-33-induced, antigen-independent murine surrogate of asthma as well as a conventional surrogate employing per-nasal challenge of mice previously sensitized to produce an IgE response to ovalbumin (OVA). In addition, in in vitro experiments we explored the direct effects of IL-33 on the proliferation and function of murine fibroblasts. Per-nasal administration of IL-33 alone was sufficient to induce airways deposition of ECMs, including collagens I, III, V and fibronectin, to a degree comparable with that observed in the OVA-sensitized and challenged mice. These changes were associated with a local imbalance between the expression of extracellular MMPs and TIMPs. Per-nasal challenge of mice with IL-33 also induced elevated airways expression of connective tissue growth factor and fibroblast growth factor receptor 4, two key facilitators of local fibrosis, again to a degree compatible with that observed in OVA-sensitized and challenged mice. Deletion of the ST2 gene, which encodes the IL-33 receptor, abrogated these fibrotic changes in the airways in the OVA surrogate. In vitro, IL-33 significantly increased the proliferation and expression of collagen III by murine lung fibroblasts. These data suggest that direct exposure of murine airways to IL-33 is able to induce local fibrotic changes, at least partially through effects of signalling through the IL-33/ST2 axis on fibroblast function and local expression of MMPs and their inhibitors, and other fibrosis-related proteins.

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“…Cytoplasmic translocation of HMGB1 in AECs was quantified as described previously . Lung biopsies were stained with periodic acid‐Schiff (PAS) reagent, and mucus hypersecretion was evaluated using a semi‐quantitative scoring system as described previously …”

Section: Methodsmentioning

confidence: 99%

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

Ullah

Vicente

Collinson

et al. 2019

Allergy

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Background Phosphoprotein associated with glycosphingolipid‐enriched microdomains 1 (PAG1) is a transmembrane adaptor protein that affects immune receptor signaling in T and B cells. Evidence from genome‐wide association studies of asthma suggests that genetic variants that regulate the expression of PAG1 are associated with asthma risk. However, it is not known whether PAG1 expression is causally related to asthma pathophysiology. Here, we investigated the role of PAG1 in a preclinical mouse model of house dust mite (HDM)‐induced allergic sensitization and allergic airway inflammation. Methods Pag1‐deficient (Pag1−/−) and wild‐type (WT) mice were sensitized or sensitized/challenged to HDM, and hallmark features of allergic inflammation were assessed. The contribution of T cells was assessed through depletion (anti‐CD4 antibody) and adoptive transfer studies. Results Type 2 inflammation (eosinophilia, eotaxin‐2 expression, IL‐4/IL‐5/IL‐13 production, mucus production) in the airways and lungs was significantly increased in HDM sensitized/challenged Pag1−/− mice compared to WT mice. The predisposition to allergic sensitization was associated with increased airway epithelial high‐mobility group box 1 (HMGB1) translocation and release, increased type 2 innate lymphoid cells (ILC2s) and monocyte‐derived dendritic cell numbers in the mediastinal lymph nodes, and increased T‐helper type 2 (TH2)‐cell differentiation. CD4+ T‐cell depletion studies or the adoptive transfer of WT OVA‐specific CD4+ T cells to WT or Pag1−/− recipients demonstrated that the heightened propensity for TH2‐cell differentiation was both T cell intrinsic and extrinsic. Conclusion PAG1 deficiency increased airway epithelial activation, ILC2 expansion, and TH2 differentiation. As a consequence, PAG1 deficiency predisposed toward allergic sensitization and increased the severity of experimental asthma.

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Chronic IL-33 expression predisposes to virus-induced asthma exacerbations by increasing type 2 inflammation and dampening antiviral immunity

Cited by 65 publications

References 57 publications

Upper Airway Cell Transcriptomics Identify a Major New Immunological Phenotype with Strong Clinical Correlates in Young Children with Acute Wheezing

Upper Airway Cell Transcriptomics Identify a Major New Immunological Phenotype with Strong Clinical Correlates in Young Children with Acute Wheezing

The effects of interleukin‐33 on airways collagen deposition and matrix metalloproteinase expression in a murine surrogate of asthma

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

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