Janine Beale and colleagues from the Imperial College and the King’s College London, UK, found that interleukin (IL)-25 is perhaps the key trigger of asthma attacks, induced by viruses, as reported in the October issue of Science Translational Medicine.
Respiratory viruses (and mostly rhinoviruses that cause the common cold) are known to be the most common triggers of asthma exacerbations. In fact, people with asthma are particularly susceptible to viral respiratory infections, which are a major cause of asthma exacerbation.
It is also known that T helper (Th)2 cell immune responses are involved in these exacerbations, but it is not known how rhinoviruses are linked to Th2 immunity, and asthma exacerbations respectively.
The UK’s research team demonstrates that rhinoviruses are able to induce IL-25 production in lung epithelial cells, and asthmatic airways have an increased propensity to produce this cytokine. The study also shows that nasal mucosa of asthmatic subjects has detectable increased IL-25 during experimental rhinovirus infection, and both baseline and infection IL-25 peak levels are significantly higher in asthma.
Thus, 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.
Of note, IL-25 (IL-17E) belongs to the IL-17 cytokine family, and is known to induce Th2 cell immune responses. This is related to the upregulation of Th2-related cytokines such as IL-4, IL-5, and IL-13 that play a central role in allergy and asthma development.
Importantly, 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.
Dr. Nathan Bartlett, the joint lead author of the study said that “airways of asthmatics are more prone to producing IL-25…… By targeting this molecule we could potentially discover a much-needed new treatment to control this potentially life-threatening reaction in asthma sufferers.”
Source: Sci Transl Med, 2014 Oct 1;6(256):256ra134. doi: 10.1126/scitranslmed.3009124.
A 2022 studyby Teresa Williams et al. reports an abundant expression and colocalization of IL-25 and IL-25 receptor at the apical surface of uninfected airway epithelial cells and rhinovirus infection increased IL-25 expression.
Previous studies have shown that epithelial cell-express IL-25 promotes allergic diseases such as asthma and is increased during viral asthma exacerbations. It is known that IL-25 stimulates type 2 inflammation and contributes to airway obstruction by triggering bronchoconstriction, mucus production, and infiltration of inflammatory cells into airways.
Teresa Williams et al. confirmed that IL-25 is constitutively expressed in vivo in human airways (endobronchial biopsies), and this was replicated in differentiated primary human BECs. The authors report an abundant constitutive expression of IL-25 protein at the apical surface airway epithelial cells from both healthy donors and subjects with asthma.
A similar expression pattern was noted for the IL-25 receptor with evidence of colocalization of IL-25 and IL-17RB. Despite the abundant constitutive expression, the investigators were able to detect increased IL-25 mRNA and protein (cell associated) expression by RV infection of ALI-BECs derived from asthmatic donors.
A 2022 systematic review and meta-analysis outlined that RV-induced asthma exacerbations are potentially caused by an imbalance between Th1 and Th2 cytokines, which may be contributed by defective innate immune responses at cellular levels.
Among asthmatic subjects with significantly increased respiratory symptoms following RV inoculation, type 2 inflammation is a significant factor contributing to RV-induced asthma exacerbations. Experimental RV infection of asthmatic subjects resulted in increased IL-4, IL-5, and IL-13 levels. The nasal and bronchial IL-5 and IL-13 levels were also positively correlated with the severity of upper and lower respiratory symptoms. Evidence suggests that IL-25 and IL-33 are key cytokines driving the type 2 inflammatory responses in asthmatic airways.
The major conclusion of this systematic review and meta-analysis is that RV-induced asthma exacerbations are potentially caused by enhanced Th2 responses (IL-4, IL-5, and IL-13), which could be promoted by IL-25 and IL-33, and IL-15 deficiency before RV infection. Also, it appears that asthmatic airway epithelial cells have defective IFNs (IFN-β and IFN-λ) production, and these changes could occur in both adults and children with atopic asthma.