NADPH oxidase-dependent reactive oxygen species mediate amplified TLR4 signaling and sepsis-induced mortality in Nrf2-deficient mice

Xiaoni Kong, Rajesh Thimmulappa, Ponvijay Kombairaju, Shyam Biswal

Research output: Contribution to journalArticlepeer-review

Abstract

Sepsis syndrome is characterized by a dysregulated inflammatory response to infection. NADPH oxidase-dependent reactive oxygen species (ROS) play significant roles in the pathophysiology of sepsis. We previously showed that disruption of Nrf2, a master regulator of antioxidant defenses, caused a dysregulation of innate immune response that resulted in greater mortality in a polymicrobial sepsis and LPS shock model; however, the underlying mechanisms are unclear. In the current study, compared with wild-type (Nrf2+/+) macrophages, we observed greater protein kinase C-induced NADPH oxidase-dependent ROS generation in Nrf2-disrupted (Nrf2-/-) macrophages that was modulated by glutathione levels. To address the NADPH oxidase-mediated hyperinflammatory response and sepsis-induced lung injury and mortality in Nrf2-/- mice, we used double knockout mice lacking Nrf2 and NADPH oxidase subunit, gp91phox (Nrf2-/-//gp91 phox-/-). Compared with Nrf2+/+ macrophages, LPS induced greater activation of TLR4 as evident by TLR4 surface trafficking and downstream recruitment of MyD88 and Toll/IL-1R domain-containing adaptor in Nrf2 -/- macrophages that was diminished by ablation of gp91 phox. Similarly, phosphorylation of IκB and IFN regulatory factor 3 as well as cytokine expression was markedly higher in Nrf2 -/- macrophages; whereas, it was similar in Nrf2+/+ and Nrf2-/-//gp91phox-/-. In vivo studies showed greater LPS-induced pulmonary inflammation in Nrf2-/- mice that was significantly reduced by ablation of gp91phox. Furthermore, LPS shock and polymicrobial sepsis induced early and greater mortality in Nrf2 -/- mice; whereas, Nrf2-/-//gp91phox-/- showed prolong survival. Together, these results demonstrate that Nrf2 is essential for the regulation of NADPH oxidase-dependent ROS-mediated TLR4 activation and lethal innate immune response in sepsis.

Original languageEnglish (US)
Pages (from-to)569-577
Number of pages9
JournalJournal of Immunology
Volume185
Issue number1
DOIs
StatePublished - Jul 1 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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