title: Negative regulation of lung inflammation and immunopathology by TNF-α 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-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. Whereas TNF-α was up-regulated in the lung after influenza infection, it was not required for normal influenza viral clearance. However, TNF-α 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-β1. Thus, in vivo neutralization of MCP-1 markedly attenuated lung immunopathology and blunted TGF-β1 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-α 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.
authors: Department of Pathology and Molecular Medicine & McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors: Daniela
authors: D
authors: Damjanovic
authors: Maziar
authors: M
authors: Divangahi
authors: Kapilan
authors: K
authors: Kugathasan
authors: Cherrie-Lee
authors: CL
authors: Small
authors: Anna
authors: A
authors: Zganiacz
authors: Earl G
authors: EG
authors: Brown
authors: Cory M
authors: CM
authors: Hogaboam
authors: Jack
authors: J
authors: Gauldie
authors: Zhou
authors: Z
authors: Xing
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001835:Body Weight; D001992:Bronchoalveolar Lavage Fluid; D018932:Chemokine CCL2 / Q000172:deficiency / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D007111:Immunity, Cellular; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D011024:Pneumonia, Viral / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha