title: FOXO transcription factors regulate innate immune mechanisms in respiratory epithelial cells.
abstract: Bacterial pathogens are a leading cause of lung infections and contribute to acute exacerbations in patients with chronic respiratory diseases. The innate immune system of the respiratory tract controls and prevents colonization of the lung with bacterial pathogens. Forkhead box transcription factor family O (FOXO) transcription factors are key regulators of cellular metabolism, proliferation, and stress resistance. In this study, our aim was to investigate the role of FOXO transcription factors in innate immune functions of respiratory epithelial cells. We show that bacterial pathogens potently activate FOXO transcription factors in cultured human respiratory epithelial cells in vitro. Infection of mice with bacterial pathogens resulted in the activation of FOXO transcription factors in alveolar and bronchial epithelial cells in vivo. Active FOXO was also detectable in human bronchial tissue obtained from subjects with different infection-related lung diseases. Small interfering RNA-mediated knockdown of FOXO in bronchial epithelial cells resulted in reduced expression of factors of the innate immune system such as antimicrobial peptides and proinflammatory cytokines, both under basal conditions and upon infection. FOXO deficiency further affected internalization of Haemophilus influenzae in bronchial epithelial cells. Finally, we show that TLR3 activates innate immune responses in a FOXO-dependent manner. In conclusion, FOXO transcription factors are involved in the cellular responses to bacterial stimuli and act as central regulators of innate immune functions in respiratory epithelial cells.
authors: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University Medical Center, 66421 Homburg/Saar, Germany.
authors: Frederik
authors: F
authors: Seiler
authors: Jan
authors: J
authors: Hellberg
authors: Philipp M
authors: PM
authors: Lepper
authors: Andreas
authors: A
authors: Kamyschnikow
authors: Christian
authors: C
authors: Herr
authors: Markus
authors: M
authors: Bischoff
authors: Frank
authors: F
authors: Langer
authors: Hans-Joachim
authors: HJ
authors: Schäfers
authors: Frank
authors: F
authors: Lammert
authors: Michael D
authors: MD
authors: Menger
authors: Robert
authors: R
authors: Bals
authors: Christoph
authors: C
authors: Beisswenger
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002908:Chronic Disease; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011552:Pseudomonas Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors