IL-1β regulates IL-33 mediated T helper 2 (Th2)-biased immunopathophysiology following respiratory syncytial virus infection in an age-dependent and caspase-1 independent manner

Abstract Respiratory syncytial virus (RSV) infection in children is a substantial clinical and health economic burden worldwide. RSV-induced immunopathophysiology has been related to age-variable IL-33 mediated Th2-biased immune responses. However, the mechanisms of the age-dependent regulation of IL-33 remain unclear. Here, we show for the first time that elevated levels of IL-33 in nasal aspirates from RSV infected human infants are associated with the disease severity. We further demonstrate the correlation of IL-33 levels with IL-1β in RSV-infected infants. IL-1β has been shown to induce expression of IL-33 in lung cells. Indeed, we found that intranasal treatment of neonatal mice with IL-1β prior to RSV infection significantly boosted the production of pulmonary IL-33. IL-33 increases coincided with an increased frequency of pulmonary type 2 innate lymphoid cells (ILC2) at 1 day post-infection (dpi) and Th2 biased immunopathophysiology after reinfection. Conversely, antagonizing IL-1β signaling in adult mice with IL-1βR antagonist (Anakinra) prior to RSV infection significantly enhanced IL-33 mediated Th2 biased immunopathophysiology after reinfection. Although it has been shown that IL-1β and IL-33 were regulated at the post-translational level by inflammasome-mediated caspase-1 activation, in our study active caspase-1 was detected exclusively within IL-33negCD45+ cells in RSV-infected lungs and was independent of age at infection. These findings suggest that IL-1β responses regulate RSV-induced IL-33 production via caspase-1 independent mechanisms in an age-dependent manner. More importantly, our findings provide the first data on respiratory IL-33 responses in RSV-infected infants.