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

Yuichi Yageta, Yukio Ishii, Yuko Morishima, Hironori Masuko, Satoshi Ano, Tadahiro Yamadori, Ken Itoh, Kaoru Takeuchi, Masayuki Yamamoto, Nobuyuki Hizawa

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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.

Original languageEnglish
Pages (from-to)4679-4690
Number of pages12
JournalJournal of virology
Volume85
Issue number10
DOIs
Publication statusPublished - 2011 May 1

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Yageta, Y., Ishii, Y., Morishima, Y., Masuko, H., Ano, S., Yamadori, T., Itoh, K., Takeuchi, K., Yamamoto, M., & Hizawa, N. (2011). Role of Nrf2 in host defense against influenza virus in cigarette smoke-exposed mice. Journal of virology, 85(10), 4679-4690. https://doi.org/10.1128/JVI.02456-10