IL-33 and Its Receptor ST2 after Inhaled Allergen Challenge in Allergic Asthmatics

Abstract

Background: Previous murine models have demonstrated interleukin (IL)-33 to be an important mediator of type-2 inflammation and to promote airway hyperresponsiveness in allergic asthma. A number of inflammatory cells produce IL-33 and eosinophils express ST2 mRNA. The relationship between IL-33 and eosinophils in allergic asthma, however, remains unclear. Objective: The aim of this work was to evaluate in vitro the effect of allergen inhalation on IL-33 levels and expression of its receptor (ST2L) on eosinophils in allergic asthmatics, and the effect of IL-33 stimulation on eosinophil activity. Methods: Plasma and sputum IL-33, soluble ST2 (sST2) levels, and ST2L expression on eosinophils were measured in 10 healthy controls and 10 allergic asthmatics. Asthmatics underwent allergen and diluent inhalation challenges. Blood and sputum samples were collected to measure IL-33, sST2, and ST2L eosinophil expression before and 24 h after allergen inhalation. Purified blood eosinophils from allergic asthmatics were incubated overnight with IL-33 to assess ST2 and intracellular IL-5 expression. Results: Baseline levels of IL-33 in sputum and sST2 in plasma and sputum were similar in allergic asthmatics compared to healthy controls. In addition, there was no difference in blood or sputum eosinophil ST2L expression in healthy controls versus allergic asthmatics. Eosinophil ST2L expression was significantly increased 24 h postallergen inhalation in allergic asthmatics. In vitro stimulation of human eosinophils with IL-33 and LPS significantly increased eosinophil ST2L expression and IL-33 stimulation increased intracellular IL-5 expression, which was attenuated by treatment with sST2 and ST2 blockade. Conclusion and Clinical Relevance: In mild asthmatics, there was a significant upregulation of ST2 surface expression on eosinophils from blood and sputum following allergen inhalation challenge. In vitro, IL-33 stimulation of eosinophils increases both ST2 membrane expression and IL-5 production. These results support a role for IL-33 in causing allergen-induced eosinophilia. Blockade of IL-33 and ST2 signaling may present a novel therapeutic avenue for asthma treatment.

Serum levels of epithelial‐derived mediators and interleukin‐4/interleukin‐13 signaling after bronchial challenge with Dermatophagoides pteronyssinus in patients with allergic asthma

“…Why the IL‐33 level does not increase after allergen exposure remains a controversial issue. Although bronchial epithelial, smooth muscle and mast cells have been identified as key sources, the principal origin of IL‐33 in allergic disease is not fully known . One assumption may be made that elevated levels of soluble ST2 receptors for IL‐33 in AA suggest localized production of this soluble form of ST2 within the airways that may act as an inhibitor of IL‐33‐induced inflammation …”

Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics

“…There is substantial evidence that the alarmins, TSLP and IL-33, play key roles in driving T2 inflammation in asthma. TSLP levels in bronchial lavage fluid and biopsies are elevated in patients with asthma compared with healthy individuals, and correlate with disease severity (including a negative correlation with lung function defined by forced expiratory volume in 1 second [FEV 1 ]) [54][55][56][57]. In addition, genetic studies of TSLP have identified alleles that are associated with asthma [58].…”

“…Additionally, patients with allergic and eosinophilic asthma phenotypes have higher serum levels of IL-33 than those with non-allergic and non-eosinophilic phenotypes [62]. Furthermore, in patients with allergic asthma, ST2 expression on eosinophils from blood and sputum is significantly upregulated after allergen inhalation challenge [54]. Higher serum soluble ST2 levels are associated with an increased risk of exacerbations [63].…”

“…Th17 polarization and subsequent IL-17 release promotes neutrophilic inflammation and a non-allergic/non-eosinophilic response [87]. TSLP, but not IL-33 or IL-25, expression in human bronchoalveolar lavage fluid has been shown to correlate most closely with neutrophil infiltration [54]. Nevertheless, future studies are warranted to understand whether there is a broader role for IL-33 in the pathogenesis of T2-low asthma.…”

Recent Advances in Clinical Allergy and Immunology

“…In order to classify asthma patients and assign them to specific, targeted therapies, biomarkers, and biomarker profiles – for example cytokines involved in asthma pathogenesis – periostin as a marker of eosinophilic inflammation that is IgE specific to certain allergens has become very important [4]. Furthermore, the expression of the interleukin (IL)-33 receptor ST2L on eosinophils, which increases significantly at 24 h postallergen inhalation in allergic asthmatics, might serve as a biomarker and is considered a therapeutic target for asthma [5]. The presence and levels of epithelium-derived cytokines in exhaled-breath condensate have been studied in patients with chronic asthma in order to identify biomarkers for asthma severity.…”