Background
Early-life respiratory viral infection is a risk factor for asthma development. Rhinovirus (RV) infection of six-day old but not mature mice causes mucous metaplasia and airway hyperresponsiveness which is associated with expansion of lung type 2 innate lymphoid cells (ILC2s) and dependent on IL-13 and the innate cytokine IL-25. However, contributions of the other innate cytokines, IL-33 and thymic stromal lymphopoietin (TSLP), to the observed asthma-like phenotype have not been examined.
Objective
We reasoned that IL-33 and TSLP expression are also induced by RV infection in immature mice and required for maximum ILC2 expansion and mucous metaplasia.
Methods
We inoculated six day-old BALB/c (wild-type) and TSLP receptor knockout (TSLPR KO) mice with sham HeLa cell lysate or RV. Selected mice were treated with neutralizing antibodies to IL-33 or recombinant IL-33, IL-25 or TSLP. ILC2s were isolated from RV-infected immature mice and treated with innate cytokines ex vivo.
Results
RV infection of six-day old mice increased IL-33 and TSLP protein abundance. TSLP expression was localized to the airway epithelium, whereas IL-33 was expressed in both epithelial and subepithelial cells. RV-induced mucous metaplasia, ILC2 expansion, airway hyperresponsiveness and epithelial cell IL-25 expression were attenuated by anti-IL-33 treatment and in TSLPR KO mice. Administration of intranasal IL-33, but not TSLP, was sufficient for mucous metaplasia. Finally, TSLP was required for maximal ILC2 gene expression in response to IL-25 and IL-33.
Conclusion
The generation of mucous metaplasia in immature, RV-infected mice involves a complex interplay between the innate cytokines IL-25, IL-33 and TSLP.