Role of Nrf2 in host defense against influenza virus in cigarette smoke-exposed mice

J Virol. 2011 May;85(10):4679-90. doi: 10.1128/JVI.02456-10. Epub 2011 Mar 2.

Abstract

Influenza virus is a common respiratory tract viral infection. Although influenza can be fatal in patients with chronic pulmonary diseases such as chronic obstructive pulmonary disease, its pathogenesis is not fully understood. The Nrf2-mediated antioxidant system is essential to protect the lungs from oxidative injury and inflammation. In the present study, we investigated the role of Nrf2 in protection against influenza virus-induced pulmonary inflammation after cigarette smoke exposure with both in vitro and in vivo approaches. For in vitro analyses, peritoneal macrophages isolated from wild-type and Nrf2-deficient mice were treated with poly(I:C) and/or cigarette smoke extract. For in vivo analysis, these mice were infected with influenza A virus with or without exposure to cigarette smoke. In Nrf2-deficient macrophages, NF-κB activation and the induction of its target inflammatory genes were enhanced after costimulation with cigarette smoke extract and poly(I:C) compared with wild-type macrophages. The induction of antioxidant genes was observed for the lungs of wild-type mice but not those of Nrf2-deficient mice after cigarette smoke exposure. Cigarette smoke-exposed Nrf2-deficient mice showed higher rates of mortality than did wild-type mice after influenza virus infection, with enhanced peribronchial inflammation, lung permeability damage, and mucus hypersecretion. Lung oxidant levels and NF-κB-mediated inflammatory gene expression in the lungs were also enhanced in Nrf2-deficient mice. Our data indicate that the antioxidant pathway controlled by Nrf2 is pivotal for protection against the development of influenza virus-induced pulmonary inflammation and injury under oxidative conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Inflammation / pathology
  • Influenza A virus / immunology*
  • Influenza A virus / pathogenicity*
  • Lung / pathology
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / virology
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / deficiency
  • NF-E2-Related Factor 2 / immunology
  • NF-E2-Related Factor 2 / metabolism*
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / mortality
  • Orthomyxoviridae Infections / pathology
  • Smoking / adverse effects*
  • Survival Analysis

Substances

  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse