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

PLoS Pathog. 2013 Feb;9(2):e1003188. doi: 10.1371/journal.ppat.1003188. Epub 2013 Feb 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / immunology
  • Acute Lung Injury / metabolism*
  • Acute Lung Injury / pathology
  • Adult
  • Animals
  • Apoptosis
  • Disease Models, Animal
  • Humans
  • Influenza, Human / immunology
  • Influenza, Human / metabolism*
  • Influenza, Human / pathology
  • Interferon-beta / metabolism*
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / metabolism*
  • Macrophages, Alveolar / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mosaicism
  • Pneumonia, Viral / immunology
  • Pneumonia, Viral / metabolism*
  • Pneumonia, Viral / pathology
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / metabolism*
  • Respiratory Mucosa / pathology
  • TNF-Related Apoptosis-Inducing Ligand / metabolism

Substances

  • TNF-Related Apoptosis-Inducing Ligand
  • Tnfsf10 protein, mouse
  • Interferon-beta

Grants and funding

This work was supported by the German Research Foundation (SFB/TR84 “Innate Immunity of the Lung” grant B2, grant LO271/4-1, and Excellence Cluster Cardio-Pulmonary System [ECCPS]), by the German Federal Ministry of Research and Education (“FluResearchNet” grants 01 KI 1006M and 01 KI 1006C and the Clinical Research Group “Infectious Diseases” grant 01 KI 0770) and by the von Behring-Röntgen Foundation of the Universities of Giessen & Marburg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.