Macrophage-expressed IFN-β Contributes to Apoptotic Alveolar Epithelial Cell Injury in Severe Influenza Virus Pneumonia

PLoS Pathogens

Peter Lewe-Schlosser¹  Juergen Lohmeyer²  Susanne Herold²  Katrin Högner²  Hans-Dieter Walmrath²  Werner Seeger²  Stefan Gattenlöhner³  Stephanie Plog⁴  Achim D. Gruber⁴  Thorsten Wolff⁵  Johannes Bodner⁶  Ulrich Kalinke⁷  Stephan Pleschka⁸  Mikhail Matrosovich⁹ 

[1] Center for Radiation Therapy, University of Giessen Lung Center (UGLC) and German Center for Lung Research (DZL), Giessen, Germany;Department of Internal Medicine II, University of Giessen Lung Center (UGLC) and German Center for Lung Research (DZL), Giessen, Germany;Department of Pathology, University of Giessen Lung Center (UGLC) and German Center for Lung Research (DZL), Giessen, Germany;Department of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany;Division of Influenza/Respiratory Viruses, Robert Koch-Institute, Berlin, Germany;Division of Thoracic Surgery, University of Giessen Lung Center (UGLC) and German Center for Lung Research (DZL), Giessen, Germany;Institute for Experimental Infection Research, Twincore Centre for Experimental and Clinical Infection Research, Hannover, Germany;Institute of Medical Virology, Justus-Liebig-University, Giessen, Germany;Institute of Virology, Philipps-University, Marburg, Germany

关键词: Apoptosis;    Alveolar macrophages;    Macrophages;    Epithelial cells;    Interferons;    Mouse models;    Transcription factors;    Pneumonia;   

DOI  :  10.1371/journal.ppat.1003188

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY