TRAIL induction in lung macrophages is IFN-ß-dependent and results in alveolar epithelial apoptosis in IV pneumonia

Introduction: Influenza virus (IV) pneumonia is characterized by rapid progression to lung failure and high mortality. Although lung macrophages have been attributed a significant role in the host defense towards IV, they are as well contributing to alveolar epithelial cell damage and lung barrier dysfunction during IV pneumonia by the release pro-apoptotic mediators such as TNF-related apoptosis-inducing ligand (TRAIL). However, the molecular signals underlying the regulation of TRAIL expression in lung macrophages upon IV infection remain elusive. Results: PR/8 infection of wild-type alveolar macrophages in vitro resulted in a dose-dependent upregulation of TRAIL mRNA and enhanced surface-expression which was largely abrogated in PKR (Protein Kinase R)-deficient macrophages. IFN-ß was released from PR/8 infected wild-type but not from PKR-deficient alveolar macrophages. Additionally NF-κB activity was impaired in PKR^-/- macrophages upon IV infection. Moreover, TRAIL mRNA was found highly upregulated in wild-type and as well in PKR-deficient alveolar macrophages upon IFN-ß stimulation. In addition, blockade of IFN-ß in the supernatant of PR/8 infected wild-type macrophages resulted in reduced TRAIL expression. Interestingly, TRAIL mRNA was upregulated on flow-sorted F4/80-positive alveolar macrophages in comparison to peripheral blood monocytes in PR/8 infected wild-type 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 significantly reduced alveolar epithelial cell apoptosis in PR/8 infected mice. Conclusion: These data demonstrate that IFN-ß released from PR/8-infected alveolar macrophages in a PKR-dependent manner is an important auto-/paracrine inducer of macrophage TRAIL expression, contributing to alveolar epithelial damage during severe IV pneumonia.