RGD Reference Report - Enhancing Nrf2 pathway by disruption of Keap1 in myeloid leukocytes protects against sepsis. - Rat Genome Database

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

Authors: Kong, X  Thimmulappa, R  Craciun, F  Harvey, C  Singh, A  Kombairaju, P  Reddy, SP  Remick, D  Biswal, S 
Citation: Kong X, etal., Am J Respir Crit Care Med. 2011 Oct 15;184(8):928-38. Epub 2011 Jul 28.
RGD ID: 6892955
Pubmed: PMID:21799073   (View Abstract at PubMed)
PMCID: PMC3208662   (View Article at PubMed Central)
DOI: DOI:10.1164/rccm.201102-0271OC   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Sepsis  ISOKeap1 (Mus musculus)6892955; 6892955 RGD 
Sepsis  IMP 6892955 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Keap1  (Kelch-like ECH-associated protein 1)

Genes (Mus musculus)
Keap1  (kelch-like ECH-associated protein 1)

Genes (Homo sapiens)
KEAP1  (kelch like ECH associated protein 1)


Additional Information