Research paperIL-33 amplifies airways inflammation in a murine surrogate of asthma putatively via activation of dendritic cells
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).
References (31)
- et al.
Diagnosis and management of T2-High asthma
J. Allergy Clin. Immunol. Pract.
(2020) - et al.
M(3) muscarinic receptor antagonist bencycloquidium bromide attenuates allergic airway inflammation, hyperresponsiveness and remodeling in mice
Eur. J. Pharmacol.
(2011) - et al.
An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow
J. Immunol. Methods
(1999) - et al.
Eosinophilic endotype of asthma
Immunol. Allergy Clin. N. Am.
(2016) - et al.
Potential autocrine regulation of interleukin-33/ST2 signaling of dendritic cells in allergic inflammation
Mucosal Immunol.
(2013) - et al.
IL-33-activated dendritic cells induce an atypical TH2-type response
J. Allergy Clin. Immunol.
(2009) - et al.
Glucocorticoid receptor translational isoforms underlie maturational stage-specific glucocorticoid sensitivities of dendritic cells in mice and humans
Blood
(2013) - Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for...
- et al.
Interleukin-33 (IL-33): a nuclear cytokine from the IL-1 family
Immunol. Rev.
(2018) - et al.
Distinct sustained structural and functional effects of interleukin-33 and interleukin-25 on the airways in a murine asthma surrogate
Immunology
(2015)
Serum IL-33 Is elevated in children with asthma and is associated with disease severity
Int. Arch. Allergy Immunol.
IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo
Am. J. Respirat. Crit. Care Med.
Elevated expression of IL-33 and TSLP in the airways of human asthmatics in vivo: a potential biomarker of severe refractory disease
J. Immunol.
Dendritic cells and the control of immunity
Nature
IL-33-activated dendritic cells are critical for allergic airway inflammation
Eur. J. Immunol.
Cited by (2)
Immunomodulatory Effect of Interleukin-33 on Dendritic Cells and Its Role in the Pathogenesis of Various Diseases
2023, Progress in Biochemistry and Biophysics