Abstract
It has been suggested that interleukin-33 (IL-33) plays an important role in the pathogenesis of asthma through a variety of pathways, but its role in airways fibrosis in asthma has not been fully elucidated. In the present study we evaluated changes in the expression of extracellular matrix proteins (ECMs) as well as matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in an IL-33-induced, antigen-independent murine surrogate of asthma as well as a conventional surrogate employing per-nasal challenge of mice previously sensitized to produce an IgE response to ovalbumin (OVA). In addition, in in vitro experiments we explored the direct effects of IL-33 on the proliferation and function of murine fibroblasts. Per-nasal administration of IL-33 alone was sufficient to induce airways deposition of ECMs, including collagens I, III, V and fibronectin, to a degree comparable with that observed in the OVA-sensitized and challenged mice. These changes were associated with a local imbalance between the expression of extracellular MMPs and TIMPs. Per-nasal challenge of mice with IL-33 also induced elevated airways expression of connective tissue growth factor and fibroblast growth factor receptor 4, two key facilitators of local fibrosis, again to a degree compatible with that observed in OVA-sensitized and challenged mice. Deletion of the ST2 gene, which encodes the IL-33 receptor, abrogated these fibrotic changes in the airways in the OVA surrogate. In vitro, IL-33 significantly increased the proliferation and expression of collagen III by murine lung fibroblasts. These data suggest that direct exposure of murine airways to IL-33 is able to induce local fibrotic changes, at least partially through effects of signalling through the IL-33/ST2 axis on fibroblast function and local expression of MMPs and their inhibitors, and other fibrosis-related proteins.