title: Critical role for IL-18 in spontaneous lung inflammation caused by autophagy deficiency.
abstract: Autophagy is an important component of the immune response. However, the functions of autophagy in human diseases are much less understood. We studied biological consequences of autophagy deficiency in mice lacking the essential autophagy gene Atg7 or Atg5 in myeloid cells. Surprisingly, these mice presented with spontaneous sterile lung inflammation, characterized by marked recruitment of inflammatory cells, submucosal thickening, goblet cell metaplasia, and increased collagen content. Lung inflammation was associated with increase in several proinflammatory cytokines in the bronchoalveolar lavage and in serum. This inflammation was largely driven by IL-18 as a result of constitutive inflammasome activation. Following i.p. LPS injection, autophagy-deficient mice had higher levels of proinflammatory cytokines in lungs and in serum, as well as increased mortality, than control mice. Intranasal bleomycin challenge exacerbated lung inflammation in autophagy-deficient mice and produced more severe fibrotic changes than in control mice. These results uncover a new and important role for autophagy as negative regulator of lung inflammation.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030; and.
authors.forename: Elmoataz
authors.initials: E
authors.lastname: Abdel Fattah
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030; and.
authors.forename: Abhisek
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Alan
authors.initials: A
authors.lastname: Herron
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030; and.
authors.forename: Zeenat
authors.initials: Z
authors.lastname: Safdar
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030; and Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030 teissa@bcm.edu.
authors.forename: N Tony
authors.initials: NT
authors.lastname: Eissa
mesh_terms: D000818:Animals; D001343:Autophagy / Q000276:immunology*; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D001761:Bleomycin / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000276:immunology; D020397:Goblet Cells / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung / Q000276:immunology / Q000473:pathology; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D011014:Pneumonia / Q000276:immunology* / Q000401:mortality / Q000473:pathology
chemical_list: C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D016207:Cytokines; D058847:Inflammasomes; D020382:Interleukin-18; D008070:Lipopolysaccharides; D008869:Microtubule-Associated Proteins; D001761:Bleomycin; D003094:Collagen; D000071193:Autophagy-Related Protein 7