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Negative regulation of lung inflammation and immunopathology by TNF-? during acute influenza infection.

ABSTRACT: Lung immunopathology is the main cause of influenza-mediated morbidity and death, and much of its molecular mechanisms remain unclear. Whereas tumor necrosis factor-? (TNF-?) 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-?-deficient mice and evaluated lung viral clearance, inflammatory responses, and immunopathology. Whereas TNF-? was up-regulated in the lung after influenza infection, it was not required for normal influenza viral clearance. However, TNF-? 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-?1. Thus, in vivo neutralization of MCP-1 markedly attenuated lung immunopathology and blunted TGF-?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-? 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.

SUBMITTER: Damjanovic D

PROVIDER: S-EPMC3260802 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other

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Negative regulation of lung inflammation and immunopathology by TNF-α during acute influenza infection.

Damjanovic Daniela D Divangahi Maziar M Kugathasan Kapilan K Small Cherrie-Lee CL Zganiacz Anna A Brown Earl G EG Hogaboam Cory M CM Gauldie Jack J Xing Zhou Z

The American journal of pathology 20111014 6

Lung immunopathology is the main cause of influenza-mediated morbidity and death, and much of its molecular mechanisms remain unclear. Whereas tumor necrosis factor-α (TNF-α) 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-α-deficient mice and evaluated lung viral clearance, inflammatory responses, and immunopathology. Wh ...[more]

PMID: 22001698

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Project description:The PB1-F2 protein encoded by influenza A viruses can contribute to virulence, a feature that is dependent of its sequence polymorphism. Whereas PB1-F2 from some H1N1 viruses were shown to exacerbate the inflammatory response within the airways, the contribution of PB1-F2 to highly pathogenic avian influenza virus (HPAIV) virulence in mammals remains poorly described. Using a H5N1 HPAIV strain isolated from duck and its PB1-F2 knocked-out mutant, we characterized the dynamics of PB1-F2-associated host response in a murine model of lethal pneumonia. The mean time of death was 10 days for the two viruses, allowing us to perform global transcriptomic analyses and detailed histological investigations of the infected lungs at multiple time points. At day 2 post-infection (pi), while no histopathological lesion was observed, PB1-F2 expression resulted in a significant inhibition of cellular pathways involved in macrophage activation and in a transcriptomic signature suggesting that it promotes damage to the epithelial barrier. At day 4 pi, the gene profile associated with PB1-F2 expression revealed dysfunctions in NK cells activity. At day 8 pi, PB1-F2 expression was strongly associated with increased transcription of genes encoding chemokines and cytokines implicated in the recruitment of granulocytes, as well as expression of a number of genes encoding enzymes expressed by neutrophils. These transcriptomic data were fully supported by the histopathological analysis of the mice lungs which evidenced more severe inflammatory lesions and enhanced recruitment of neutrophils in the context of PB1-F2 expression, and thus provided a functional corroboration to the insight obtained in this work. In summary, our study shows that PB1-F2 of H5N1 HPAIV markedly influences the expression of the host transcriptome in a different way than its H1N1 counterparts: H5N1 PB1-F2 first delays the initial immune response but increases the pulmonary inflammatory response during the late stages of infection.

Dataset Information

Negative regulation of lung inflammation and immunopathology by TNF-? during acute influenza infection.

Publications

Negative regulation of lung inflammation and immunopathology by TNF-α during acute influenza infection.

Similar Datasets

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