Article
Macrophage TRAIL expression is IFN-β-dependent and mediates alveolar epithelial apoptosis and barrier dysfunction in influenza virus pneumonia
Die Expression von TRAIL in Makrophagen ist IFN-β-abhängig und führt zu Apoptose von alveolären Epithelzellen und zu einer Schrankenstörung bei der Influenza Pneumonie
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Published: | June 2, 2010 |
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Introduction: Influenza virus (IV) pneumonia occasionally progresses to acute lung injury (ALI/ARDS). Although alveolar macrophages (AM) have been attributed a significant role in the host defense towards IV, they were shown to contribute to lung injury progression by release of pro-inflammatory mediators and cytokines such as the pro-apoptotic TNF-related apoptosis-inducing ligand (TRAIL). However, the molecular signals underlying the regulation of macrophage TRAIL and its epithelially expressed receptor DR5 upon IV infection remain elusive.
Methods and results: IV (PR/8, H1N1; x31, H3N2) infection ex vivo resulted in transcriptional and translational upregulation of TRAIL in murine and human primary alveolar macrophages (AM), and in enhanced expression of DR5 in human and murine isolated type I AEC (qRT-PCR, FACS). IV-induced TRAIL upregulation was dependent on protein kinase R (PKR)-mediated NF-қB activation, and on resulting auto-/paracrine interferon-β (IFN-β) released from AM and AEC, as demonstrated by use of PKR-deficient AM and specific inhibitors. Additionally, TRAIL was upregulated on FACS-separated F4/80-positive AM in PR/8 infected C57BL/6 mice in vivo at day 8 post infection when PR/8 was largely cleared and type I IFN levels were increased in lung homogenates. Finally, abrogation of TRAIL signalling resulted in delayed IV clearance, however significantly reduced AEC apoptosis, alveolar leakage and mortality in PR/8 infected mice.
Conclusion: These data demonstrate that IFN-β released from PR/8-infected AM and AEC in a PKR-NF-қB-dependent manner is an important auto-/paracrine inducer of macrophage TRAIL expression significantly contributing to loss of alveolar epithelial barrier integrity during severe IV pneumonia. Future in vivo studies using gene-targeted mice will reveal the putative effect of TRAIL-inducers PKR and IFN-β on barrier function and IV clearance.
DFG, grant SFB 547; BMBF, Clinical Research Group “Infectious Diseases” 01 KI 0770.