PMID- 22001698 OWN - NLM STAT- MEDLINE DCOM- 20120209 LR - 20220318 IS - 1525-2191 (Electronic) IS - 0002-9440 (Print) IS - 0002-9440 (Linking) VI - 179 IP - 6 DP - 2011 Dec TI - Negative regulation of lung inflammation and immunopathology by TNF-alpha during acute influenza infection. PG - 2963-76 LID - 10.1016/j.ajpath.2011.09.003 [doi] AB - 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-beta1. Thus, in vivo neutralization of MCP-1 markedly attenuated lung immunopathology and blunted TGF-beta1 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. CI - Copyright (c) 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. FAU - Damjanovic, Daniela AU - Damjanovic D AD - Department of Pathology and Molecular Medicine & McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada. FAU - Divangahi, Maziar AU - Divangahi M FAU - Kugathasan, Kapilan AU - Kugathasan K FAU - Small, Cherrie-Lee AU - Small CL FAU - Zganiacz, Anna AU - Zganiacz A FAU - Brown, Earl G AU - Brown EG FAU - Hogaboam, Cory M AU - Hogaboam CM FAU - Gauldie, Jack AU - Gauldie J FAU - Xing, Zhou AU - Xing Z LA - eng GR - Canadian Institutes of Health Research/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20111014 PL - United States TA - Am J Pathol JT - The American journal of pathology JID - 0370502 RN - 0 (Ccl2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Chemokines) RN - 0 (Cytokines) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Adaptive Immunity MH - Animals MH - Body Weight MH - Bronchoalveolar Lavage Fluid MH - Chemokine CCL2/deficiency/metabolism MH - Chemokines/metabolism MH - Cytokines/metabolism MH - Immunity, Cellular MH - Influenza A Virus, H1N1 Subtype/*immunology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Orthomyxoviridae Infections/*immunology MH - Pneumonia, Viral/*immunology MH - T-Lymphocytes/immunology MH - Tumor Necrosis Factor-alpha/deficiency/metabolism/*physiology PMC - PMC3260802 EDAT- 2011/10/18 06:00 MHDA- 2012/02/10 06:00 PMCR- 2012/12/01 CRDT- 2011/10/18 06:00 PHST- 2011/07/13 00:00 [received] PHST- 2011/08/22 00:00 [revised] PHST- 2011/09/01 00:00 [accepted] PHST- 2011/10/18 06:00 [entrez] PHST- 2011/10/18 06:00 [pubmed] PHST- 2012/02/10 06:00 [medline] PHST- 2012/12/01 00:00 [pmc-release] AID - S0002-9440(11)00850-9 [pii] AID - 10.1016/j.ajpath.2011.09.003 [doi] PST - ppublish SO - Am J Pathol. 2011 Dec;179(6):2963-76. doi: 10.1016/j.ajpath.2011.09.003. Epub 2011 Oct 14.