title: IL13 activates autophagy to regulate secretion in airway epithelial cells.
abstract: Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagy-related 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent.
authors.affiliation: a Department of Medicine , Washington University , St. Louis , MO , USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Dickinson
authors.affiliation: a Department of Medicine , Washington University , St. Louis , MO , USA.
authors.forename: Yael
authors.initials: Y
authors.lastname: Alevy
authors.affiliation: b Department of Pathology and Immunology , Washington University , St. Louis , MO , USA.
authors.forename: Nicole P
authors.initials: NP
authors.lastname: Malvin
authors.affiliation: b Department of Pathology and Immunology , Washington University , St. Louis , MO , USA.
authors.forename: Khushbu K
authors.initials: KK
authors.lastname: Patel
authors.affiliation: a Department of Medicine , Washington University , St. Louis , MO , USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Gunsten
authors.affiliation: a Department of Medicine , Washington University , St. Louis , MO , USA.|c Department of Cell Biology , Washington University , St. Louis , MO , USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
authors.affiliation: b Department of Pathology and Immunology , Washington University , St. Louis , MO , USA.|d Department of Developmental Biology , Washington University , St. Louis , MO , USA.
authors.forename: Thaddeus S
authors.initials: TS
authors.lastname: Stappenbeck
authors.affiliation: a Department of Medicine , Washington University , St. Louis , MO , USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Brody
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5 / Q000172:deficiency / Q000378:metabolism; D000071183:Autophagy-Related Proteins / Q000378:metabolism; D001980:Bronchi / Q000166:cytology*; D002352:Carrier Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D020397:Goblet Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D006984:Hypertrophy; D018793:Interleukin-13 / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D055271:Mucin 5AC; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C539000:ATG14 protein, human; C502778:ATG5 protein, human; D033942:Adaptor Proteins, Vesicular Transport; C532820:Atg16l1 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018793:Interleukin-13; D055271:Mucin 5AC; D017382:Reactive Oxygen Species
keywords: IL13; MUC5AC; airway epithelial cells; autophagy; reactive oxygen species; secretion