title: Enhancing Nrf2 pathway by disruption of Keap1 in myeloid leukocytes protects against sepsis.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Xiaoni
authors.initials: X
authors.lastname: Kong
authors.forename: Rajesh
authors.initials: R
authors.lastname: Thimmulappa
authors.forename: Florin
authors.initials: F
authors.lastname: Craciun
authors.forename: Christopher
authors.initials: C
authors.lastname: Harvey
authors.forename: Anju
authors.initials: A
authors.lastname: Singh
authors.forename: Ponvijay
authors.initials: P
authors.lastname: Kombairaju
authors.forename: Sekhar P
authors.initials: SP
authors.lastname: Reddy
authors.forename: Daniel
authors.initials: D
authors.lastname: Remick
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D007113:Immunity, Innate; D015151:Immunoblotting; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018805:Sepsis / Q000276:immunology / Q000517:prevention & control*; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D018836:Inflammation Mediators; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4