Axl receptor blockade ameliorates pulmonary pathology resulting from primary viral infection and viral exacerbation of asthma.

Viruses use Tyro3, Axl, and Mertk (TAM) receptor tyrosine kinases to infect and modulate the immune properties of various cell types, which led us to investigate whether TAM receptor activation affected primary viral infection and viral exacerbation of asthma in experimental models. In these lung-specific models, we observed that Axl was the most abundantly induced TAM receptor protein. During primary respiratory syncytial virus (RSV) infection, anti-Axl mAb treatment significantly increased the number of IFN-γ-producing T cells and NK cells and significantly suppressed RSV replication and whole lung levels of IL-4 and IL-13. Intrapulmonary H1N1 infection induced lethal pulmonary inflammation, but anti-Axl mAb treatment of infected mice significantly increased the number of IFN-β-producing macrophages and dendritic cells and significantly suppressed neutrophil infiltration. Consequently, the lethal effect of H1N1 infection in this model was significantly reduced in the mAb-treated group compared with the IgG control-treated group. Targeting Axl also inhibited airway hyperresponsiveness, IL-4 and IL-13 production, and goblet cell metaplasia in an Aspergillus fumigatus-induced asthma model. Finally, infection of mice with RSV during fungal asthma significantly exacerbated airway inflammation, goblet cell metaplasia, and airway remodeling, but all of these features in this viral exacerbation model were ameliorated by anti-Axl mAb treatment. Taken together, these results demonstrate that Axl modulates the pulmonary immune response during viral and/or allergic pathology, and they also suggest that targeting this TAM receptor might provide a novel therapeutic approach in these infectious diseases.