Innate immunity drives asthma or chronic bronchitis phenotypes after viral infection

In human disease, respiratory infection with paramyxovirus can promote asthma or chronic bronchitis. To investigate the unknown mechanism for these chronic phenotypes, this thesis used a mouse model of post-viral goblet cell metaplasia (GCM) and airway hyper-reactivity (AHR), two hallmarks of human asthma and chronic bronchitis/chronic obstructive pulmonary disease (COPD). In this mouse model, Interleukin-13 (IL-13) blockade prevented chronic (i.e., day 49 post-infection) GCM and AHR. Surprisingly, macrophages were the major source of chronic IL-13. Macrophage depletion with clodronate liposomes reduced chronic GCM. As demonstrated by CD1d-deficient mice, NKT cells were necessary for IL-13 production by macrophages. DNA microarrays led to the discovery that IL-13 receptor (IL13Ralpha1) was up-regulated on IL-13+ macrophages after viral infection; IL-13 blockade prevented the development of IL-13+ macrophages. In a positive feedback loop, IL-13 signaling prompted more IL-13 production by macrophages. Glucocorticoid steroid is a major treatment for human asthma or COPD. In the post-viral mouse model, steroid fully suppressed chronic GCM (90% reduction) and partially suppressed AHR (50% reduction); so, steroid partially segregated GCM from AHR. After steroid treatment, IL-13+ macrophages and IL-13 were greatly reduced. Early treatment with steroid, before the development of IL-13+ macrophages, reduced GCM in mice with macrophage-specific deficiency of glucocorticoid receptor (MGR KO mice). However, late treatment with steroid, after the development of IL-13+ macrophages, failed to reduce levels of IL-13 and GCM in MGR KO mice. Late treatment with steroid directly targets macrophages. This thesis corroborated the murine results in human disease. Unlike normal controls, human subjects with COPD had IL-13+ macrophages in the lung. Glucocorticoid steroid treatment of human asthmatics suppressed and partially segregated GCM and AHR, as in the murine model. This thesis presents an unusual role for innate immunity in asthma and chronic bronchitis. Innate immunity drives a chronic phenotype without repeated stimuli from the environment. This novel NKT-macrophage-IL-13 axis is susceptible to steroid treatment and may be a target for therapeutic intervention in chronic inflammatory diseases of the airway.