Rationale: Rhinoviruses are the major cause of asthma
exacerbations; however, its underlying mechanisms are poorly
understood. We hypothesized that the epithelial cell–derived
cytokine IL-33 plays a central role in exacerbation pathogenesis
through augmentation of type 2 inflammation.
Objectives: To assess whether rhinovirus induces a type 2
inflammatory response in asthma in vivo and to define a role for IL-33
in this pathway.
Methods: We used a human experimental model of rhinovirus
infection and novel airway sampling techniques to measure IL-4, IL-5,
IL-13, and IL-33 levels in the asthmatic and healthy airways during
a rhinovirus infection. Additionally, we cultured human T cells and type
2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirusinfected
bronchial epithelial cells (BECs) to assess type 2 cytokine
production in the presence or absence of IL-33 receptor blockade.
Measurements and Main Results: IL-4, IL-5, IL-13, and IL-33 are
all induced by rhinovirus in the asthmatic airway in vivo and relate to
exacerbation severity. Further, induction of IL-33 correlates with
viral load and IL-5 and IL-13 levels. Rhinovirus infection of human
primary BECs induced IL-33, and culture of human T cells and ILC2s
with supernatants of rhinovirus-infected BECs strongly induced
type 2 cytokines. This induction was entirely dependent on IL-33.
Conclusions: IL-33 and type 2 cytokines are induced during
a rhinovirus-induced asthma exacerbation in vivo. Virus-induced
IL-33 and IL-33–responsive T cells and ILC2s are key mechanistic
links between viral infection and exacerbation of asthma. IL-33
inhibition is a novel therapeutic approach for asthma exacerbations