title: Lack of autophagy induces steroid-resistant airway inflammation.
abstract: Neutrophilic corticosteroid-resistant asthma accounts for a significant proportion of asthma; however, little is known about the mechanisms that underlie the pathogenesis of the disease.
  
  
  
  We sought to address the role of autophagy in lung inflammation and the pathogenesis of corticosteroid-resistant neutrophilic asthma.
  
  
  
  We developed CD11c-specific autophagy-related gene 5 (Atg5)(-/-) mice and used several murine models to investigate the role of autophagy in asthmatic patients.
  
  
  
  For the first time, we found that deletion of the Atg5 gene specifically in CD11c(+) cells, which leads to impairment of the autophagy pathway, causes unprovoked spontaneous airway hyperreactivity and severe neutrophilic lung inflammation in mice. We found that severe lung inflammation impairs the autophagy pathway, particularly in pulmonary CD11c(+) cells in wild-type mice. We further found that adoptive transfer of Atg5(-/-), but not wild-type, bone marrow-derived dendritic cells augments lung inflammation with increased IL-17A levels in the lungs. Our data indicate that neutrophilic asthma in Atg5(-/-) mice is glucocorticoid resistant and IL-17A dependent.
  
  
  
  Our results suggest that lack of autophagy in pulmonary CD11c(+) cells induces neutrophilic airway inflammation and hyperreactivity.
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Hadi
authors.initials: H
authors.lastname: Maazi
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Ishwarya
authors.initials: I
authors.lastname: Sankaranarayanan
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lam
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Bryant
authors.initials: B
authors.lastname: Khoo
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, San Diego, Calif.
authors.forename: Pejman
authors.initials: P
authors.lastname: Soroosh
authors.affiliation: Division of Pulmonary and Critical Care, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Barbers
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: J-H
authors.initials: JH
authors.lastname: James Ou
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif. Electronic address: akbari@usc.edu.
authors.forename: Omid
authors.initials: O
authors.lastname: Akbari
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000276:immunology; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000235:genetics; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002452:Cell Count; D016207:Cytokines / Q000276:immunology; D003907:Dexamethasone / Q000627:therapeutic use*; D004351:Drug Resistance; D005260:Female; D008168:Lung / Q000166:cytology / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039981:Pyroglyphidae / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D016207:Cytokines; D003907:Dexamethasone
keywords: Autophagy; asthma; corticosteroid-resistance asthma; lung inflammation; neutrophilic asthma