Elsevier

Cellular Immunology

Volume 366, August 2021, 104395
Cellular Immunology

Research paper
IL-33 amplifies airways inflammation in a murine surrogate of asthma putatively via activation of dendritic cells

https://doi.org/10.1016/j.cellimm.2021.104395Get rights and content

Highlights

  • Mice challenged with Der f and IL-33 evinced more airway inflammation than Der f alone.

  • IL-33 induced airways inflammation of mice exposed to sub-threshold dosages of Der f.

  • Dendritic cells activated by IL-33 are more functional.

Abstract

Although contributions of IL-33 to pulmonary diseases, including asthma, have been well documented, the complexity of such regulation warrants additional exploration. To better understand the involvement of IL-33, we used a murine asthma surrogate based on sensitisation and challenge with dust mite extract in the presence/absence of IL-33. Murine models were established with Dermatophagoides farinae (Der f) to establish (1) the effect of co-administered rmIL-33; (2) the effect of prior glucocorticoid intervention; (3) the effect of IL-33 on challenge with sub-threshold dosage Der f. The effects of rmIL-33 on bone marrow-derived dendritic cells were explored in vitro. Mice challenged with Der f combined with IL-33 compared with diluent control evinced significantly more airways inflammation and local cytokine production which was less sensitive to inhibition by dexamethasone. IL-33 also induced airways hyperresponsiveness, eosinophilic inflammation and cytokine production in lung tissues of animals exposed to sub-threshold dosage of Der f. In vitro, IL-33-stimulated DCs showed a significantly elevated capacity to stimulate CD4+ T cell proliferation and cytokine production and were also significantly more resistant to dexamethasone-induced apoptosis. Our data suggest that IL-33 reduces the threshold for allergen-induced inflammation of the airways in acorticosteroid-resistant fashion possibly in part through acting on DCs, a phenomenon which may be relevant to the development of severe, corticosteroid-resistant airways obstruction in human asthmatic patients.

Introduction

Asthma is a global health issue, with 400,000 deaths attributed to the disease every year [1]. Asthma is regarded as a disease characterised partly by inflammation of the airways mucosa which, if extensive and resistant to therapy, may cause severe symptoms and potentially life-threatening airways obstruction. This inflammation in most patients with asthma is characterised by a predominantly Th2 type immune response, leading to an inflammatory cellular infiltrate abundant in eosinophils [2]. Numerous recent studies have implicated IL-33 in the pathogenesis of airways inflammation in asthma [3], [4], [5], [6], [7]. Extracellular IL-33 acts via its cognate receptor ST2, expressed on a variety of immune cells, including macrophages, dendritic cells, group 2 innate lymphoid cells (ILC2) and others [3], and signals via the canonical IL-1R signalling cascade, thus promoting production of Th2-type cytokines. It has been shown that children with asthma have elevated serum concentrations of IL-33 to a degree which correlates with the severity of their disease [5]. IL-33 also plays a critical role in exacerbation of asthma induced by respiratory viral infection [6]. Another of our previous studies has also demonstrated that the concentration of IL-33 in bronchoalveolar lavage fluid (BALF) from patients with asthma is prominently elevated to a degree which correlates with disease severity [7].

It is well accepted that dendritic cells (DCs) are the major professional antigen presenting cells, serving as a hub for initiating and shaping the nature of the immune response through processing of antigens and presentation of derived peptides to specific T cells in the form of MHC class II-peptide complexes [8]. IL-33, along with other cytokines such as thymic stromal lymphopoietin (TSLP) have been shown to induce OX40L on dendritic cells, which is the key molecular switch for Th2-type T cell differentiation [9]. In addition, although both IL-25 and IL-33 induced OX40L on DCs in vitro, it seems only IL-33 signalling to be necessary for mite and peanut allergic sensitization [10]. Given these observations, we here address the hypothesis that, at least partly through activation of DCs, IL-33 reduces the threshold for the induction of allergen-induced, Th2-type inflammation of the airways and that this phenomenon is glucocorticoid resistant.

Section snippets

Animalsand preparation of murine surrogates

Female BALB/c mice (6–8 weeks old; 17–20 g; Vital River Laboratory, Beijing, China) were housed in a pathogen-free environment in the Department of Laboratory Animal Sciences, Capital Medical University, Beijing, China. Animal experiments were approved by the Institutional Animal Care and Use Committee of Capital Medical University (AEEI-2016–153). To evaluate whether IL-33 is associated with the occurrence of severe asthma, murine asthma surrogates were established as follows. On days 0 and

Effects of IL-33 on lung function and airways inflammatory cellular infiltration of mice challenged with a pathogenic dosage of Der f in the presence/absence of dexamethasone intervention

Compared with the controls, the mean total resistance of the respiratory system (Rrs) was significantly increased in mice challenged with both Der f alone and Der f + IL-33, with no significant difference between the two groups (Fig. 1B). Further intervention with dexamethasone again did not significantly alter the mean Rrs of the mice challenged either with Der f alone or along with IL-33 (Fig. 1B). The mean total number of BALF cells was significantly elevated in mice challenged with Der f

Discussion

Asthma is a complex disease involving bronchial mucosal inflammation the aetiology and characteristics of which likely vary between patients [16]. In the present study we address and support the hypothesis that IL-33 contributes to the pathogenesis of asthmatic airways inflammation not only by enhancing, in a glucocorticoid resistant fashion, the pro-inflammatory activities of environmental triggers of airways inflammation such as inhaled aeroallergens, but also by reducing the threshold of

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (81670032, 81870032, 81770049, 81971510, 82071805), the National Key Research and Development Program of China (2016YFC0901102), the National Science &Technology Pillar Program during the Twelfth Five-year Plan Period (2012BAI05B02) and the Natural Science Foundation of Beijing Municipality (7192023).

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