NK cells in asthma exacerbation

Lunding, Lars; Wegmann, Michael

We therefore hypothesized that stimulation of TLR3/RIG-I could be a critical event in the pathogenesis of acute, virus-induced asthma exacerbations. In order to test this hypothesis we delivered the synthetic TLR3/RIG-I ligand poly IC to the lungs of mice sensitized to ovalbumin (OVA) after experimental allergic asthma has been established by inhalation of an OVA-aerosol. Indeed, this “second hit” resulted in acute worsening of the disease by points of mucus production, lung function, and airway inflammation. Interestingly, the inflammatory infiltrate was not only characterized by significantly enhanced numbers of eosinophils but also by a pronounced influx of neutrophils, which have been attributed to corticosteroid-resistant asthma. The aggravated inflammatory response was further associated with elevated production of various cytokines including typical T helper 2 (TH2) type cytokines and TH17 type cytokines such as interleukin (IL) 17A. Using IL-17A deficient animals we could demonstrate that this cytokine is essential for the induction of poly IC-triggered exacerbation of experimental asthma in mice and subsequently we went on to identify the cellular source of IL-17A. After in-vitro restimulation we found increased numbers of TH17 cells in the lungs of mice with experimental asthma exacerbation. Adoptive transfer experiments in mice demonstrated that proinflammatory TH17 cells are capable of aggravating already established experimental asthma towards a corticosteroid-resistant phenotype by triggering neutrophil infiltration into the airways. However, since our protocol for the induction of an experimental asthma exacerbation also successfully worked in IL-23p19 deficient animals, which do not display mature, proinflammatory TH17 cells, we doubted the critical importance of TH17 in our model [3]. We therefore used homozygous Rorc-GFP mice that do not express functional RORγt and therefore are incapable to produce TH17 cells [4]. Again local application of poly IC aggravated allergic airway inflammation and induced airway neutrophilia in these mice, so that TH17 can definitely be excluded to be the pathologically relevant source of IL-17A in our model.