Autophagy functions in lung macrophages and dendritic cells to regulate allergen-dependent inflammatory responses.

Asthma affects 260 million people worldwide, with severe asthma cases that are associated with TH17/TH1 responses and neutrophil dominated inflammation being the most difficult to treat due to corticosteroid insensitivity. Single nucleotide polymorphisms in the ATG5 gene, which encodes for a protein required for the cellular recycling process of autophagy, are associated with higher risk for developing severe asthma. However, the role for ATG5 during allergic inflammation remains mostly unknown. We have identified an autophagy-dependent role for ATG5 in lung macrophages and dendritic cells (DCs) for suppressing TH17 responses and neutrophil accumulation in house dust mite (HDM)-challenged mice, a TH17/TH1 dominated model for allergic airway inflammation due to contamination of the HDM with lipopolysaccharide. In contrast, autophagy was required to promote eosinophil accumulation in the TH2-dominated ovalbumin model of allergic airway inflammation, supporting a model where autophagy functions in lung macrophages and DCs to suppress TH17 responses and promote TH2 responses in an allergen-dependent manner. In addition, we discover that autophagy is also required in macrophages exposed to HDM to suppress the secretion of cytokines and chemokines that would otherwise recruit neutrophils to the lungs, independent of T cell responses. Together, our data identify multiple roles for autophagy in suppressing the neutrophil accumulation in lungs that is associated with severe asthma.