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.
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.
Authors: Christopher J Harvey; Rajesh K Thimmulappa; Sanjay Sethi; Xiaoni Kong; Lonny Yarmus; Robert H Brown; David Feller-Kopman; Robert Wise; Shyam Biswal Journal: Sci Transl Med Date: 2011-04-13 Impact factor: 17.956
Authors: Corinne Alberti; Christian Brun-Buisson; Hilmar Burchardi; Claudio Martin; Sergey Goodman; Antonio Artigas; Alberto Sicignano; Mark Palazzo; Rui Moreno; Ronan Boulmé; Eric Lepage; Roger Le Gall Journal: Intensive Care Med Date: 2001-12-04 Impact factor: 17.440
Authors: G R Bernard; J L Vincent; P F Laterre; S P LaRosa; J F Dhainaut; A Lopez-Rodriguez; J S Steingrub; G E Garber; J D Helterbrand; E W Ely; C J Fisher Journal: N Engl J Med Date: 2001-03-08 Impact factor: 91.245
Authors: Rajesh K Thimmulappa; Kim H Mai; Sorachai Srisuma; Thomas W Kensler; Masayuki Yamamoto; Shyam Biswal Journal: Cancer Res Date: 2002-09-15 Impact factor: 12.701
Authors: Nancy Chou MacGarvey; Hagir B Suliman; Raquel R Bartz; Ping Fu; Crystal M Withers; Karen E Welty-Wolf; Claude A Piantadosi Journal: Am J Respir Crit Care Med Date: 2012-02-03 Impact factor: 21.405
Authors: Sanjeev Noel; Maria N Martina; Samatha Bandapalle; Lorraine C Racusen; Haranatha R Potteti; Abdel R A Hamad; Sekhar P Reddy; Hamid Rabb Journal: J Am Soc Nephrol Date: 2015-08-20 Impact factor: 10.121