NK cells in asthma exacerbation

Asthma management typically aims at maintaining asthma control by using corticosteroids that suppress airway inflammation. However, acute asthma exacerbations often occur leading to loss of control and necessitating systemic corticosteroids, hospitalization, or even both. Consequently, acute asthma exacerbations have a major impact on the mortality and morbidity of asthma as well as on the medical costs associated with the disease [1]. Although the development of new medications to reduce the frequency and severity of acute asthma exacerbations has advanced recently, an incomplete understanding of the immuno-pathogenetic mechanisms underlying these episodes of spontaneous worsening still limits their development. Epidemiological surveys suggested respiratory viral infections as the most common triggers of asthma exacerbation [2]. In most cases these viral infections are caused by rhino viruses and respiratory syncytial virus, while infections with influenza virus, human metapneumovirus, corona virus, or parainfluenza viruses have been recorded less frequently [2]. All these viruses have in common that their genome is encoded on single-stranded (ss) RNA, which in turn is recognized by the vertebrate immune system via toll-like receptor 3 (TLR3) and retinoic acid induced gene I (RIG-I). 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 …