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Approximately 85% of asthma exacerbations, also known as asthma attacks, are triggered by respiratory viruses and are characterized by an elevated type 2 immune response. Beale et al. now show that infection with rhinoviruses, the most common type of respiratory virus, is associated with increased expression of interleukin-25 (IL-25), an initiator and regulator of the T helper cell type 2 (TH2) immune response. Importantly, they showed in mice that blocking IL-25 signalling can reduce the rhinovirus-induced TH2 response, and might thus reduce the number and severity of asthma exacerbations.
In this study, human bronchial epithelial cells (BECs) were infected ex vivo with rhinovirus. Upon infection, IL25 mRNA levels were upregulated about tenfold more in BECs from atopic asthmatic individuals than they were from non-asthmatic individuals; baseline levels were not significantly different between these two groups. When experimentally infected with rhinovirus, asthmatic volunteers also produced more IL-25 in their nasal mucosal fluid than did non-asthmatic volunteers.
To investigate the contribution of IL-25 upregulation to rhinovirus-induced asthma exacerbations, the authors used a mouse model in which systemic administration of ovalbumin protein (to induce allergic sensitization) is followed by intranasal administration of ovalbumin together with rhinovirus (to mimic an exacerbation of allergic asthma). Mice sensitized and challenged with ovalbumin had higher levels of Il25 mRNA in their bronchioalveolar lavages than did non-allergic mice, and subsequent infection with rhinovirus further increased Il25 mRNA levels — to about 28-fold the levels seen in allergic, mock-infected mice. In immunohistological lung sections, IL-25 protein staining was increased in allergic, infected mice in both epithelial cells and in infiltrating IL25+ inflammatory cells, suggesting multiple sources for this cytokine during asthma exacerbations.
IL-25 production by epithelial cells early in the infection could start an amplification loop
By comparing data from time points early and late after infection, the authors suggest IL-25 production by epithelial cells early in the infection could start an amplification loop by recruiting IL-25-producing inflammatory cells, which further increase the production of IL-25 and type 2 cytokines. Correspondingly, levels of type 2 cytokines, including IL-4, IL-5 and IL-13, were also increased in bronchioalveolar lavages from sensitized, infected mice.
The authors then used an IL-25 receptor (IL-17RB)-specific antibody to further define the role of IL-25 in this process. Blocking IL-17RB around the time of rhinovirus infection in allergic mice prevented the levels of IL-4, IL-5 and IL-13 from increasing. The IL17RB-specific antibody also reduced mucous secretion and the airway neutrophil, eosinophil and lymphocyte responses in allergic, infected mice.
Notably, the IL-17RB-specific antibody also reduced viral load 10 hours after infection. Type 2 immune responses are believed to interfere with antiviral responses, so inhibiting the IL-25 signalling pathway could serve two functions: increasing the antiviral response and decreasing virus-exacerbated allergic inflammation.
Overall, these data provide evidence that IL-25 and its receptor could be important targets for the treatment of rhinovirus-induced asthma exacerbations.
References
Beale, J. et al. Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation. Sci. Transl. Med. 6, 256ra134 (2014)
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Cully, M. IL-25 blockade could reduce virus-associated asthma attacks. Nat Rev Drug Discov 13, 811 (2014). https://doi.org/10.1038/nrd4473
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DOI: https://doi.org/10.1038/nrd4473