3.2 Interleukin-33 (IL-33)
Binding to and signaling through its ST2 receptor, IL-33 drives the production of Th2-associated cytokines in asthma and other allergic diseases but also acts as ILC2 activator during viral infections [45-47]. In infants <2 years of age, hospitalized with bronchiolitis during the RSV season, increased amounts of IL-33 were detected in the upper airways, more frequently in infants with RSV and HRV coinfections than in those with either infection alone [41]. In BALB/c mice intranasal inoculation with RSV induced IL-33 and IL-13 production, and increased eosinophil recruitment in the lung [48]. In these animals, production of IL-13 occurred involving the IL-33/ST2 pathway, since incubation of lung cells with anti-ST2 antibody diminished IL-13-producing cell frequency [48]. To further determine the role of IL-33 in activating ILC2 during RSV infection, a study on wild-type and IL-33 KO mice was performed [43]. On day 4 after infection, both wild-type and IL-33 KO mice showed a significant inflammatory response to RSV, with a significant and similar increase in the total numbers of lung IL-13+ ILC2. However, IL-13 concentrations were significantly lower in RSV-infected IL-33 KO mice than in RSV-infected wild-type mice [43], highlighting the role for IL-33 in ILC2 activation. Age-variable effects of alarmins on ILC2 can also explain why chronological age at time of infection, is an important risk factor for severe RSV bronchiolitis [1]. In the lungs of neonatal, but not of adult mice, infection with RSV induced a rapid IL-33 expression and an increase in ILC2 numbers [49]. Administration of IL-33 to adult mice during RSV infection induced lung disease, whereas blocking IL-33 with antibodies during infection or using IL-33 receptor KO neonatal mice inhibited Th2 inflammation, airway hyperresponsiveness and mucus overproduction [49]. In this study, wild-type mice were reinfected with RSV at 4 weeks post-primary infection. In neonatal mice, neutralizing IL-33 with antibodies during primary infection resulted in significantly reductions of Th2 inflammation and airway hyperresponsiveness following RSV reinfection [49]. Moreover, adoptive transfer of ILC2 from donor wild-type mice or administration of IL‐33 to IL-33-deficient mice was crucial for the development of airway inflammation and hyperresponsiveness following RSV infection [50].