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Macrophage-expressed IFN-ß contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia.

Högner, Katrin; Wolff, Thorsten; Pleschka, Stephan; Plog, Stephanie; Gruber, Achim D; Kalinke, Ulrich; Walmrath, Hans-Dieter; Bodner, Johannes; Gattenlöhner, Stefan; Lewe-Schlosser, Peter; Matrosovich, Mikhail; Seeger, Werner; Lohmeyer, Juergen; Herold, Susanne.
PLoS Pathog; 9(2): e1003188, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23468627
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-ß 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-ß 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-ß 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-ß-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury.
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