Lung epithelial apoptosis in influenza virus pneumonia : the role of macrophage-expressed TNF-related apoptosis-inducing ligand

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2008
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Herold, Susanne
Steinmueller, Mirko
von Wulffen, Werner
Cakarova, Lidija
Pinto, Ruth
Pleschka, Stephan
Kuziel, William A.
Corazza, Nadia
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Journal of Experimental Medicine. 2008, 205(13), pp. 3065-3077. ISSN 0022-1007. eISSN 1540-9538. Available under: doi: 10.1084/jem.20080201
Zusammenfassung

Mononuclear phagocytes have been attributed a crucial role in the host defense toward influenza virus (IV), but their contribution to influenza-induced lung failure is incompletely understood. We demonstrate for the first time that lung-recruited “exudate” macrophages significantly contribute to alveolar epithelial cell (AEC) apoptosis by the release of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in a murine model of influenza-induced pneumonia. Using CC-chemokine receptor 2–deficient (CCR2−/−) mice characterized by defective inflammatory macrophage recruitment, and blocking anti-CCR2 antibodies, we show that exudate macrophage accumulation in the lungs of influenza-infected mice is associated with pronounced AEC apoptosis and increased lung leakage and mortality. Among several proapoptotic mediators analyzed, TRAIL messenger RNA was found to be markedly up-regulated in alveolar exudate macrophages as compared with peripheral blood monocytes. Moreover, among the different alveolar-recruited leukocyte subsets, TRAIL protein was predominantly expressed on macrophages. Finally, abrogation of TRAIL signaling in exudate macrophages resulted in significantly reduced AEC apoptosis, attenuated lung leakage, and increased survival upon IV infection. Collectively, these findings demonstrate a key role for exudate macrophages in the induction of alveolar leakage and mortality in IV pneumonia. Epithelial cell apoptosis induced by TRAIL-expressing macrophages is identified as a major underlying mechanism.

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ISO 690HEROLD, Susanne, Mirko STEINMUELLER, Werner VON WULFFEN, Lidija CAKAROVA, Ruth PINTO, Stephan PLESCHKA, Matthias MACK, William A. KUZIEL, Nadia CORAZZA, Thomas BRUNNER, Werner SEEGER, Juergen LOHMEYER, 2008. Lung epithelial apoptosis in influenza virus pneumonia : the role of macrophage-expressed TNF-related apoptosis-inducing ligand. In: Journal of Experimental Medicine. 2008, 205(13), pp. 3065-3077. ISSN 0022-1007. eISSN 1540-9538. Available under: doi: 10.1084/jem.20080201
BibTex
@article{Herold2008-12-22epith-14261,
  year={2008},
  doi={10.1084/jem.20080201},
  title={Lung epithelial apoptosis in influenza virus pneumonia : the role of macrophage-expressed TNF-related apoptosis-inducing ligand},
  number={13},
  volume={205},
  issn={0022-1007},
  journal={Journal of Experimental Medicine},
  pages={3065--3077},
  author={Herold, Susanne and Steinmueller, Mirko and von Wulffen, Werner and Cakarova, Lidija and Pinto, Ruth and Pleschka, Stephan and Mack, Matthias and Kuziel, William A. and Corazza, Nadia and Brunner, Thomas and Seeger, Werner and Lohmeyer, Juergen}
}
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