title: Macrophage-expressed IFN-β contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia.
abstract: Influenza viruses (IV) cause pneumonia in humans with progression to lung failure and fatal outcome. Dysregulated release of cytokines including type I interferons (IFNs) has been attributed a crucial role in immune-mediated pulmonary injury during severe IV infection. Using ex vivo and in vivo IV infection models, we demonstrate that alveolar macrophage (AM)-expressed IFN-β significantly contributes to IV-induced alveolar epithelial cell (AEC) injury by autocrine induction of the pro-apoptotic factor TNF-related apoptosis-inducing ligand (TRAIL). Of note, TRAIL was highly upregulated in and released from AM of patients with pandemic H1N1 IV-induced acute lung injury. Elucidating the cell-specific underlying signalling pathways revealed that IV infection induced IFN-β release in AM in a protein kinase R- (PKR-) and NF-κB-dependent way. Bone marrow chimeric mice lacking these signalling mediators in resident and lung-recruited AM and mice subjected to alveolar neutralization of IFN-β and TRAIL displayed reduced alveolar epithelial cell apoptosis and attenuated lung injury during severe IV pneumonia. Together, we demonstrate that macrophage-released type I IFNs, apart from their well-known anti-viral properties, contribute to IV-induced AEC damage and lung injury by autocrine induction of the pro-apoptotic factor TRAIL. Our data suggest that therapeutic targeting of the macrophage IFN-β-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury.
authors.affiliation: Department of Internal Medicine II, University of Giessen Lung Center, Giessen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Högner
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wolff
authors.forename: Stephan
authors.initials: S
authors.lastname: Pleschka
authors.forename: Stephanie
authors.initials: S
authors.lastname: Plog
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Walmrath
authors.forename: Johannes
authors.initials: J
authors.lastname: Bodner
authors.forename: Stefan
authors.initials: S
authors.lastname: Gattenlöhner
authors.forename: Peter
authors.initials: P
authors.lastname: Lewe-Schlosser
authors.forename: Mikhail
authors.initials: M
authors.lastname: Matrosovich
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Juergen
authors.initials: J
authors.lastname: Lohmeyer
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D006801:Humans; D007251:Influenza, Human / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016899:Interferon-beta / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009030:Mosaicism; D011024:Pneumonia, Viral / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D016899:Interferon-beta