Macrophage-epithelial interactions during influenza virus pneumonia : Alveolar recruitment pathways and impact on epithelial barrier integrity
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Influenza A virus pneumonia is characterized by rapid progression to lung failure and high mortality. During early stages of infection significant amounts of leukocytes accumulate within the lung parenchyma including peripheral blood monocytes/macrophages, neutrophils and lymphocytes. Among these, macrophages have been attributed a crucial role in the host defense towards influenza virus (IV). In contrast, the precise transepithelial recruitment pathways of peripheral blood monocytes into the alveolar air space and the potential contribution of alveolarly accumulating ("exudate") macrophages to alveolar epithelial damage and lung barrier dysfunction during IV pneumonia has not yet been adequately addressed. Therefore, the present thesis investigated the chemokine-receptor involvement during IV-induced transepithelial monocyte migration in vitro and in vivo. Infection of primary murine alveolar epithelial cells with the mouse-adapted influenza A virus strain PR/8 markedly induced the release of the monocyte chemoattractants CCL2 and CCL5 followed by a strong monocyte transepithelial migration. This monocyte migratory response was strictly dependent on monocyte CCR2 but not CCR5 chemokine receptor expression. Moreover, using CCR2-deficient mice and function blocking anti-CCR2 antibodies in an IV pneumonia model, it was demonstrated that alveolar macrophage accumulation was solely dependent on monocyte-expressed CCR2 in vivo. In addition, the contribution of lung exudate macrophages to alveolar leakage formation during lethal IV pneumonia was delineated. Exudate macrophage accumulation in the lungs of PR/8 infected wildtype mice was associated with increased alveolar epithelial cell apoptosis, lung leakage and mortality. All these features of acute lung injury were strongly reduced in CCR2-/- mice and in wildtype mice treated with function blocking anti-CCR2 antibodies. Among several proapoptotic mediators analysed, TNF-related apoptosis-inducing ligand (TRAIL) gene expression was found to be markedly upregulated in alveolar exudate macrophages as compared to peripheral blood monocytes. Moreover, among the different alveolar recruited leukocyte subsets, TRAIL protein was predominantly expressed on macrophages. Finally, repetitive treatment of IV-infected mice with a monoclonal anti-TRAIL antibody resulted in significant reduction of alveolar epithelial cell apoptosis, attenuated alveolar leakage and significantly increased survival. Collectively, these findings demonstrate a major role of the CCL2/CCR2 axis in monocyte transepithelial migration. Additionally, CCR2-dependently recruited exudate macrophages were shown to be key players in the induction of alveolar leakage and mortality in influenza virus pneumonia, with macrophage TRAIL expression-linked epithelial apoptosis being recognized as major underlying mechanism and potential treatment target.Verknüpfung zu Publikationen oder weiteren Datensätzen
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J. Immunol., 177, 2006, S.1817-24