L65
Impairment of Autophagy in Pulmonary CD11c+ Cells Induces Corticosteroid-Unresponsive Airway Hyperreactivity
Monday, March 7, 2016: 2:30 PM
Room 403A (Convention Center)
Hadi Maazi, PhD, , , , ,
Rationale: A significant proportion of asthmatic patients do not respond to steroid therapy and suffer from neutrophilic asthma with incompletely understood pathogenesis. Autophagy is an important intracellular organelle recycling pathway that has been implicated in asthma. We evaluated the role of autophagy in the pathogenesis of steroid-resistant neutrophilic asthma. 

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.

Conclusions:

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.