Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 179, Issue 6, Pages 2963-2976Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2011.09.003
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Funding
- Ontario Thoracic Society
- Canadian Institutes for Health Research
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Lung immunopathology is the main cause of influenza-mediated morbidity and death, and much of its molecular mechanisms remain unclear. Whereas tumor necrosis factor-alpha (TNF-alpha) is traditionally considered a proinflammatory cytokine, its role in influenza immunopathology is unresolved. We have investigated this issue by using a model of acute H1N1 influenza infection established in wild-type and TNF-alpha deficient mice and evaluated lung viral clearance, inflammatory responses, and immunopathology. Whereas TNF-alpha was up-regulated in the lung after influenza infection, it was not required for normal influenza viral clearance. However, TNF-alpha deficiency led not only to a greater extent of illness but also to heightened lung immunopathology and tissue remodeling. The severe lung immunopathology was associated with increased inflammatory cell infiltration, anti-influenza adaptive immune responses, and expression of cytokines such as monocyte chemoattractant protein-1 (MCP-1) and fibrotic growth factor, TGF-beta 1. Thus, in vivo neutralization of MCP-1 markedly attenuated lung immunopathology and blunted TGF-beta 1 production following influenza infection in these hosts. On the other hand, in vivo transgenic expression of MCP-1 worsened lung immunopathology following influenza infection in wild-type hosts. Thus, TNF-alpha is dispensable for influenza clearance; however, different from the traditional belief, this cytokine is critically required for negatively regulating the extent of lung immunopathology during acute influenza infection. (Ant J Pathol 2011, 179:2963-2976; DOI: 10.1016/j.ajpath.2011.09.003)
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