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].