Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

Abstract

Lung immunopathology is the main cause of influenzamediated 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.

Pregnancy outcome and clinical status of gilts following experimental infection by H1N2, H3N2 and H1N1pdm09 influenza A viruses during the last month of gestation

“…The results of another study indicate that mice lacking IL-6 are less likely to survive the infection by this means, implying a beneficial effect of IL-6 in controlling the infection [26]. Tumor necrosis factor-a is probably essential for limitation of lung lesions during acute influenza virus infection [27]. In general, the plasma level of TNF-a increased after infection in the current experiments.…”

Influenza A (H1N1) virus infection triggers severe pulmonary inflammation in lupus-prone mice following viral clearance

“…Concurrently, these mice also had more IAV specific TNFα producing T cells, more total TNFα in the lung, and fewer neutrophils. During influenza infection, a deficiency in TNFα, specifically soluble TNFα, is known to increase morbidity and immunopathology in the lung suggesting TNFα acts as a strong immunoregulator during infection [30, 52]. Further, it was found TNFα was important during IAV infection for directing a more proficient CD8+ T cell response although TNFα was dispensable for viral clearance [30, 52].…”

Infectious agents involved in reproduction failure in swine

“…W warunkach terenowych w przebiegu grypy świń obserwowano ronienia, jak również zwiększoną liczbę martwo urodzonych prosiąt (10,14,52,53). Uważa się, że ronienia na tle zakażenia SIV mogą być wynikiem zarówno wysokiej gorączki i wydzielanych cytokin prozapalnych, jak i transplacentarnej transmisji wirusa, aczkolwiek niewiele jest w piśmiennictwie danych na ten temat.…”