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

被引:300
作者
Herold, Susanne [1 ]
Steinmueller, Mirko [1 ]
von Wulffen, Werner [1 ]
Cakarova, Lidija [1 ]
Pinto, Ruth [2 ]
Pleschka, Stephan [2 ]
Mack, Matthias [3 ]
Kuziel, William A. [4 ]
Corazza, Nadia [5 ]
Brunner, Thomas [5 ]
Seeger, Werner [1 ]
Lohmeyer, Juergen [1 ]
机构
[1] Univ Giessen, Lung Ctr, Dept Internal Med, Div Pulm & Crit Care Med & Infect Dis, D-35390 Giessen, Germany
[2] Univ Giessen, Inst Med Virol, D-35390 Giessen, Germany
[3] Univ Regensburg Klinikum, Dept Internal Med, D-93042 Regensburg, Germany
[4] PDL BioPharma Inc, Redwood City, CA 94063 USA
[5] Univ Bern, Div Immunopathol, Inst Pathol, CH-3010 Bern, Switzerland
关键词
D O I
10.1084/jem.20080201
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:3065 / 3077
页数:13
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