Enhancing Nrf2 pathway by disruption of Keap1 in myeloid leukocytes protects against sepsis

Xiaoni Kong, Rajesh Thimmulappa, Florin Craciun, Christopher Harvey, Anju Singh, Ponvijay Kombairaju, Sekhar P. Reddy, Daniel Remick, Shyam Biswal

Research output: Contribution to journalArticle

Abstract

Rationale: Sepsis syndrome is characterized by inappropriate amplified systemic inflammatory response and bacteremia that promote multiorgan failure and mortality. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates a pleiotropic cytoprotective defense program including antioxidants and protects against several inflammatory disorders by inhibiting oxidative tissue injuries. However, the role of enhanced Nrf2 activity in modulating innate immune responses to microbial infection and pathogenesis of sepsis is unclear. Objectives: To determine whether Nrf2 in myeloid leukocytes alters inflammatory response and protects against sepsis. Methods: Mice with deletion of Nrf2 or kelch-like ECH-associated protein (Keap1) in myeloid leukocyte cells and respective floxed controls were subjected to cecal ligation and puncture-induced sepsis and were assessed for survival, organ injury, systemic inflammation, and bacteremia. Using LPS-stimulated peritoneal macrophages, Toll-like receptor (TLR) 4 surface trafficking and downstream signaling events were analyzed. Measurements and Main Results: Mortality, organ injury, circulating levels of inflammatory mediators, and bacteremia were markedly reduced in LysM-Keap1 -/- compared with respective floxed controls (Keap1 f/f or Nrf2 f/f) and significantly elevated in LysM-Nrf2 -/- mice after cecal ligation and puncture. Peritoneal macrophages from septic LysM-Keap1 -/- mice showed a greater bacterial phagocytic activity compared with LysM-Nrf2 -/- and floxed controls. LPS stimulation resulted in greater reactive oxygen species-induced cell surface transport of TLR4 from trans-Golgi network and subsequent TLR4 downstream signaling (recruitment of MYD88 and TRIF, phosphorylation of IkB and IRF3, and cytokine expression) in macrophages of LysM-Nrf2 -/- compared with LysM-Keap1 -/- mice and floxed controls. Conclusions: Our study shows that Nrf2 acts as a critical immunomodulator in leukocytes, controls host inflammatory response to bacterial infection, and protects against sepsis.

Original languageEnglish (US)
Pages (from-to)928-938
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume184
Issue number8
DOIs
StatePublished - Oct 15 2011

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Sepsis
Leukocytes
Bacteremia
Peritoneal Macrophages
Punctures
Ligation
Wounds and Injuries
trans-Golgi Network
Tissue Survival
Systemic Inflammatory Response Syndrome
Toll-Like Receptor 4
Mortality
Immunologic Factors
Myeloid Cells
Bacterial Infections
Innate Immunity
Reactive Oxygen Species
Antioxidants
Macrophages
Phosphorylation

Keywords

  • Antioxidants
  • Inflammation
  • Keap1
  • Nrf2
  • Sepsis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Enhancing Nrf2 pathway by disruption of Keap1 in myeloid leukocytes protects against sepsis. / Kong, Xiaoni; Thimmulappa, Rajesh; Craciun, Florin; Harvey, Christopher; Singh, Anju; Kombairaju, Ponvijay; Reddy, Sekhar P.; Remick, Daniel; Biswal, Shyam.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 184, No. 8, 15.10.2011, p. 928-938.

Research output: Contribution to journalArticle

Kong, Xiaoni ; Thimmulappa, Rajesh ; Craciun, Florin ; Harvey, Christopher ; Singh, Anju ; Kombairaju, Ponvijay ; Reddy, Sekhar P. ; Remick, Daniel ; Biswal, Shyam. / Enhancing Nrf2 pathway by disruption of Keap1 in myeloid leukocytes protects against sepsis. In: American Journal of Respiratory and Critical Care Medicine. 2011 ; Vol. 184, No. 8. pp. 928-938.
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abstract = "Rationale: Sepsis syndrome is characterized by inappropriate amplified systemic inflammatory response and bacteremia that promote multiorgan failure and mortality. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates a pleiotropic cytoprotective defense program including antioxidants and protects against several inflammatory disorders by inhibiting oxidative tissue injuries. However, the role of enhanced Nrf2 activity in modulating innate immune responses to microbial infection and pathogenesis of sepsis is unclear. Objectives: To determine whether Nrf2 in myeloid leukocytes alters inflammatory response and protects against sepsis. Methods: Mice with deletion of Nrf2 or kelch-like ECH-associated protein (Keap1) in myeloid leukocyte cells and respective floxed controls were subjected to cecal ligation and puncture-induced sepsis and were assessed for survival, organ injury, systemic inflammation, and bacteremia. Using LPS-stimulated peritoneal macrophages, Toll-like receptor (TLR) 4 surface trafficking and downstream signaling events were analyzed. Measurements and Main Results: Mortality, organ injury, circulating levels of inflammatory mediators, and bacteremia were markedly reduced in LysM-Keap1 -/- compared with respective floxed controls (Keap1 f/f or Nrf2 f/f) and significantly elevated in LysM-Nrf2 -/- mice after cecal ligation and puncture. Peritoneal macrophages from septic LysM-Keap1 -/- mice showed a greater bacterial phagocytic activity compared with LysM-Nrf2 -/- and floxed controls. LPS stimulation resulted in greater reactive oxygen species-induced cell surface transport of TLR4 from trans-Golgi network and subsequent TLR4 downstream signaling (recruitment of MYD88 and TRIF, phosphorylation of IkB and IRF3, and cytokine expression) in macrophages of LysM-Nrf2 -/- compared with LysM-Keap1 -/- mice and floxed controls. Conclusions: Our study shows that Nrf2 acts as a critical immunomodulator in leukocytes, controls host inflammatory response to bacterial infection, and protects against sepsis.",
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AU - Singh, Anju

AU - Kombairaju, Ponvijay

AU - Reddy, Sekhar P.

AU - Remick, Daniel

AU - Biswal, Shyam

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N2 - Rationale: Sepsis syndrome is characterized by inappropriate amplified systemic inflammatory response and bacteremia that promote multiorgan failure and mortality. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates a pleiotropic cytoprotective defense program including antioxidants and protects against several inflammatory disorders by inhibiting oxidative tissue injuries. However, the role of enhanced Nrf2 activity in modulating innate immune responses to microbial infection and pathogenesis of sepsis is unclear. Objectives: To determine whether Nrf2 in myeloid leukocytes alters inflammatory response and protects against sepsis. Methods: Mice with deletion of Nrf2 or kelch-like ECH-associated protein (Keap1) in myeloid leukocyte cells and respective floxed controls were subjected to cecal ligation and puncture-induced sepsis and were assessed for survival, organ injury, systemic inflammation, and bacteremia. Using LPS-stimulated peritoneal macrophages, Toll-like receptor (TLR) 4 surface trafficking and downstream signaling events were analyzed. Measurements and Main Results: Mortality, organ injury, circulating levels of inflammatory mediators, and bacteremia were markedly reduced in LysM-Keap1 -/- compared with respective floxed controls (Keap1 f/f or Nrf2 f/f) and significantly elevated in LysM-Nrf2 -/- mice after cecal ligation and puncture. Peritoneal macrophages from septic LysM-Keap1 -/- mice showed a greater bacterial phagocytic activity compared with LysM-Nrf2 -/- and floxed controls. LPS stimulation resulted in greater reactive oxygen species-induced cell surface transport of TLR4 from trans-Golgi network and subsequent TLR4 downstream signaling (recruitment of MYD88 and TRIF, phosphorylation of IkB and IRF3, and cytokine expression) in macrophages of LysM-Nrf2 -/- compared with LysM-Keap1 -/- mice and floxed controls. Conclusions: Our study shows that Nrf2 acts as a critical immunomodulator in leukocytes, controls host inflammatory response to bacterial infection, and protects against sepsis.

AB - Rationale: Sepsis syndrome is characterized by inappropriate amplified systemic inflammatory response and bacteremia that promote multiorgan failure and mortality. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates a pleiotropic cytoprotective defense program including antioxidants and protects against several inflammatory disorders by inhibiting oxidative tissue injuries. However, the role of enhanced Nrf2 activity in modulating innate immune responses to microbial infection and pathogenesis of sepsis is unclear. Objectives: To determine whether Nrf2 in myeloid leukocytes alters inflammatory response and protects against sepsis. Methods: Mice with deletion of Nrf2 or kelch-like ECH-associated protein (Keap1) in myeloid leukocyte cells and respective floxed controls were subjected to cecal ligation and puncture-induced sepsis and were assessed for survival, organ injury, systemic inflammation, and bacteremia. Using LPS-stimulated peritoneal macrophages, Toll-like receptor (TLR) 4 surface trafficking and downstream signaling events were analyzed. Measurements and Main Results: Mortality, organ injury, circulating levels of inflammatory mediators, and bacteremia were markedly reduced in LysM-Keap1 -/- compared with respective floxed controls (Keap1 f/f or Nrf2 f/f) and significantly elevated in LysM-Nrf2 -/- mice after cecal ligation and puncture. Peritoneal macrophages from septic LysM-Keap1 -/- mice showed a greater bacterial phagocytic activity compared with LysM-Nrf2 -/- and floxed controls. LPS stimulation resulted in greater reactive oxygen species-induced cell surface transport of TLR4 from trans-Golgi network and subsequent TLR4 downstream signaling (recruitment of MYD88 and TRIF, phosphorylation of IkB and IRF3, and cytokine expression) in macrophages of LysM-Nrf2 -/- compared with LysM-Keap1 -/- mice and floxed controls. Conclusions: Our study shows that Nrf2 acts as a critical immunomodulator in leukocytes, controls host inflammatory response to bacterial infection, and protects against sepsis.

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