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 T_H17 and T_H1 responses and neutrophil-dominated inflammation being the most difficult to treat due to corticosteroid insensitivity. Single nucleotide polymorphisms in the ATG5 gene, which codes for a protein required for the cellular recycling process of macroautophagy/autophagy, are associated with higher risk for developing severe asthma. We explored the mechanistic basis for the genetic association of ATG5 variants with severe asthma. We identified an autophagy-dependent role for ATG5 in lung macrophages and dendritic cells (DCs) for suppressing T_H17 responses and neutrophil accumulation in house dust mite (HDM)-challenged mice, a T_H17- and T_H1-dominated model for allergic airway inflammation due to contamination of the HDM with residual lipopolysaccharide. In contrast, autophagy was required to promote eosinophil accumulation in the T_H2-dominated ovalbumin model of allergic airway inflammation, supporting a model where autophagy functions in lung macrophages and DCs to suppress T_H17 responses and promote T_H2 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 T-cell-dependent and -independent ways autophagy in innate immune cells suppresses the neutrophil accumulation in lungs that is associated with severe asthma.Abbreviations: AHR: airway hyperresponsiveness; BAL: bronchoalveolar lavages; BMDM: bone marrow-derived macrophages; CSF3/G-CSF: colony stimulating factor 3; DCs: dendritic cells; H&E: hematoxylin and eosin; HDM: house dust mites; i.n.: intranasal/intranasally; i.p.: intraperitoneal/intraperitoneally; Jax: The Jackson Laboratory; KC: keratinocyte-derived chemokine; LPS: lipopolysaccharide; MHC: major histocompatibility complex; OVA: ovalbumin; PAMPs: pathogen-associated molecular patterns; PAS: periodic acid-Schiff; SNP: single-nucleotide polymorphism.