title: SAM-pointed domain ETS factor mediates epithelial cell-intrinsic innate immune signaling during airway mucous metaplasia.
abstract: Airway mucus plays a critical role in clearing inhaled toxins, particles, and pathogens. Diverse toxic, inflammatory, and infectious insults induce airway mucus secretion and goblet cell metaplasia to preserve airway sterility and homeostasis. However, goblet cell metaplasia, mucus hypersecretion, and airway obstruction are integral features of inflammatory lung diseases, including asthma, chronic obstructive lung disease, and cystic fibrosis, which cause an immense burden of morbidity and mortality. These chronic lung diseases are united by susceptibility to microbial colonization and recurrent airway infections. Whether these twinned phenomena (mucous metaplasia, compromised host defenses) are causally related has been unclear. Here, we demonstrate that SAM pointed domain ETS factor (SPDEF) was induced by rhinoviral infection of primary human airway cells and that cytoplasmic activities of SPDEF, a transcriptional regulator of airway goblet cell metaplasia, inhibited Toll-like receptor (TLR) activation of epithelial cells. SPDEF bound to and inhibited activities of TLR signaling adapters, MyD88 and TRIF, inhibiting MyD88-induced cytokine production and TRIF-induced interferon β production. Conditional expression of SPDEF in airway epithelial cells in vivo inhibited LPS-induced neutrophilic infiltration and bacterial clearance. SPDEF-mediated inhibition of both TLR and type I interferon signaling likely protects the lung against inflammatory damage when inciting stimuli are not eradicated. Present findings provide, at least in part, a molecular explanation for increased susceptibility to infection in lung diseases associated with mucous metaplasia and a mechanism by which patients with florid mucous metaplasia may tolerate microbial burdens that are usually associated with fulminant inflammatory disease in normal hosts.
authors.affiliation: Division of Neonatology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Korfhagen
authors.forename: Joseph
authors.initials: J
authors.lastname: Kitzmiller
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Anusha
authors.initials: A
authors.lastname: Sridharan
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Haitchi
authors.forename: Rashmi S
authors.initials: RS
authors.lastname: Hegde
authors.forename: Senad
authors.initials: S
authors.lastname: Divanovic
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Karp
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015153:Blotting, Western; D004318:Doxycycline / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D018793:Interleukin-13 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008171:Lung Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008679:Metaplasia; D051379:Mice; D018613:Microscopy, Confocal; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012229:Rhinovirus / Q000502:physiology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000900:Anti-Bacterial Agents; D018793:Interleukin-13; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D050783:Proto-Oncogene Proteins c-ets; C403974:SPDEF protein, human; C470409:TICAM1 protein, human; D051193:Toll-Like Receptors; D004318:Doxycycline