Abstract
Rhinoviruses (RVs), which are the most common cause of virally induced asthma exacerbations, account for much of the burden of asthma in terms of morbidity, mortality, and associated cost. Interleukin-25 (IL-25) activates type 2-driven inflammation and is therefore potentially important in virally induced asthma exacerbations. To investigate this, we examined whether RV-induced IL-25 could contribute to asthma exacerbations. RV-infected cultured asthmatic bronchial epithelial cells exhibited a heightened intrinsic capacity for IL-25 expression, which correlated with donor atopic status. In vivo human IL-25 expression was greater in asthmatics at baseline and during experimental RV infection. In addition, in mice, RV infection induced IL-25 expression and augmented allergen-induced IL-25. Blockade of the IL-25 receptor reduced many RV-induced exacerbation-specific responses including type 2 cytokine expression, mucus production, and recruitment of eosinophils, neutrophils, basophils, and T and non-T type 2 cells. Therefore, asthmatic epithelial cells have an increased intrinsic capacity for expression of a pro-type 2 cytokine in response to a viral infection, and IL-25 is a key mediator of RV-induced exacerbations of pulmonary inflammation.
Highlights
IntroductionAsthma attacks (exacerbations) are the most clinically and economically important form of this disease
Asthma attacks are the most clinically and economically important form of this disease
Mouse models of allergic asthma exacerbation have demonstrated the capacity of RV infection to augment Th2 responses and associated features of allergic airways disease such as airway hyperreactivity (AHR) and mucus production[12, 13]
Summary
Asthma attacks (exacerbations) are the most clinically and economically important form of this disease. Many studies have detected increased type-2 cells[3, 4] and type-2 cytokines[5, 6] in asthma. We studied exacerbations in a human experimental RV infection model in allergic asthmatic and normal volunteers and demonstrated that asthmatics had more severe lower respiratory tract symptoms, reductions in lung function and increases in bronchial hyper-reactivity. Mouse models of allergic asthma exacerbation have demonstrated the capacity of RV infection to augment Th2 responses and associated features of allergic airways disease such as airway hyperreactivity (AHR) and mucus production[12, 13]. Bronchial epithelium is likely to be critical for this interaction since it responds to both allergen[14] and RV infection[15] and has the capacity to produce cytokines that are potent activators of type-2 immunity such as IL-25(16)
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