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Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand
Open accessAbstract
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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“However, the strategies for differentiation of resident macrophage subsets in the airways and lung tissues are insufficient to distinguish AMs from lung interstitial macrophages or inflammatory monocytic cells invading the lung in response to infections.”
From Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections (2013) · cites this paper as [17]
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Metadata
- Authors
- Herold, S., Steinmueller, M., von Wulffen, W., Cakarova, L., Pinto, R., Pleschka, S., Mack, M., Kuziel, W. A., Corazza, N., Brunner, T., Seeger, W., & Lohmeyer, J.
- Affiliations
- Justus-Liebig-Universität Gießen (DE)
- 1University of Giessen Lung Center, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Infectious Diseases,
- University of Regensburg (DE)
- 4PDL BioPharma Inc., Redwood City, CA 94063
- University of Bern (CH)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2008-12-08
- Volume
- 205
- Issue
- 13
- Pages
- 3065-3077
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2605231
- OpenAlex
- W2105053798
- Cited by
- 376
- References
- 44
- Citations by year
- 2026: 3 · 2025: 19 · 2024: 16 · 2023: 17 · 2022: 26 · 2021: 32 · 2020: 32 · 2019: 16 · 2018: 21 · 2017: 21 · 2016: 23 · 2015: 20 · 2014: 21 · 2013: 21 · 2012: 22
- FWCI
- 15.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- KOPS (University of Konstanz) (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- influenza virus pneumonia, alveolar epithelial cell apoptosis, TRAIL, tumor necrosis factor-related apoptosis-inducing ligand, CCR2, macrophage recruitment, respiratory failure, host defense
- MeSH terms
- Animals, Bronchoalveolar Lavage Fluid, Chimera, Humans, Influenza, Human, Leukocytes, Mononuclear, Lung, Macrophages, Mice, Inbred C57BL, Orthomyxoviridae, Phagocytes, Pneumonia, Apoptosis, Mice, Knockout, Respiratory Mucosa, Apoptosis Regulatory Proteins, Mice, TNF-Related Apoptosis-Inducing Ligand, Receptors, CCR2
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