Methods: We assessed the airway hyperreactivity (AHR) and inflammation, T cell response and DC profile in several autophagy impaired mouse models. We also generated a novel mouse model in which Atg5, a key gene in autophagy pathway, is specifically knocked out in CD11c+ cells.
Results: Our results show that induction of severe asthma impairs autophagy pathway in lung CD11c+ cell. We found for the first time that house dust mite (HDM)-mediated induction of AHR and lung inflammation in Atg5-/- mice leads to neutrophilic steroid resistance asthma while in WT mice causes eosinophilic steroid-responsive asthma. Adoptive transfer of bone-marrow derived CD11c+ cells from ATG5-/- but not WT mice is sufficient to mediate Th17-dependent neutrophilic asthma in WT recipients. Most importantly, we found that CD11c-specific Atg5-/- mice develop spontaneous AHR and neutrophilic lung inflammation. Lack of autophagy in CD11c+ cells induces significantly higher level of key cytokines such as IL-1a, IL-1b and IL-23.
Our results provide novel insights into an important and previously unrecognized role of autophagy in asthma and suggest that inducing autophagy may affect pulmonary CD11c+ cells function and therefore, may be considered as an attractive clinical target for future strategies of treatment and prevention of asthma.