C-Kit inhibitors prevent respiratory viral infection-induced acute asthma via the blockade of innate lymphoid cell activation

Abstract

Abstract Asthma is a major public health problem that affects nearly 10% of the general population and is thought to be mediated by allergen-specific Th2 cells, adaptive immunity and allergic inflammation. Current treatments for asthma generally focus on minimizing the Th2-driven eosinophilic inflammation with the use of anti-inflammatory therapies such as corticosteroids. However, this approach, targeting the adaptive Th2 cell immunity with corticosteroids, has not reduced the high rates of hospitalizations for acute asthma, most often caused by acute viral infection, including influenza. Recently, type 2 innate lymphoid cells (ILC2) expressing c-Kit have been shown to expand during influenza infection and directly caused airway hyper reactivity (AHR), a cardinal feature of asthma. We now show that the treatment of influenza-infected mice with c-Kit kinase inhibitors blocked the development of AHR and airway inflammation and greatly reduced the number and function of ILC2 cells, whereas the treatment with corticosteroids, commonly used to treat acute asthma, failed to prevent the influenza-induced AHR. We also demonstrated that c-Kit function is required for normal ILC2 cell function and for influenza-induced AHR, and that c-Kit kinase inhibitor inhibits murine lung ILC2 cell proliferation and cytokine productions in vitro and in vivo. Furthermore, the treatment of c-Kit inhibitor did not affect in vivo viral clearance. Our study demonstrated the crucial role of c-Kit in modulating the ILC2 activation in the lungs, particularly in respiratory viral infection induced acute asthma.