IL-1β Promotes Expansion of IL-33+ Lung Epithelial Stem Cells Following RSV Infection During Infancy.

Respiratory syncytial virus (RSV)-induced immunopathogenesis and disease severity in neonatal mice and human infants have been related to elevated pulmonary IL-33. Thus, targeting IL-33 has been suggested as a potential therapy for respiratory viral infections. Yet, the regulatory mechanisms on IL-33 during early life remain unclear. Here, using a neonatal mouse model of RSV, we demonstrate that IL-1β positively regulates but is not required for RSV-induced expression of pulmonary IL-33 in neonatal mice early after the initial infection. Exogenous IL-1β upregulates RSV-induced IL-33 expression by promoting the proliferation of IL-33pos lung epithelial stem/progenitor cells (EpiSPC). These cells are exclusively detected in RSV-infected neonatal rather than adult mice, partially explaining the IL-1β-independent IL-33 expression in RSV-infected adult mice. Furthermore, IL-1β aggravates IL-33 mediated Th2 biased immunopathogenesis upon reinfection. Collectively, our study demonstrates that IL-1β exacerbates IL-33 mediated RSV immunopathogenesis by promoting the proliferation of IL-33pos EpiSPC in early life.