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PMID: 16585964 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis.

The Journal of clinical investigation ·Vol. 116 ·No. 4 ·2006-04-00 ·Pages 984-95

Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW, Biswal S

Abstract

Host genetic factors that regulate innate immunity determine susceptibility to sepsis. Disruption of nuclear factor-erythroid 2-related factor 2 (Nrf2), a basic leucine zipper transcription factor that regulates redox balance and stress response, dramatically increased the mortality of mice in response to endotoxin- and cecal ligation and puncture-induced septic shock. LPS as well as TNF-alpha stimulus resulted in greater lung inflammation in Nrf2-deficient mice. Temporal analysis of pulmonary global gene expression after LPS challenge revealed augmented expression of large numbers of proinflammatory genes associated with the innate immune response at as early as 30 minutes in lungs of Nrf2-deficient mice, indicating severe immune dysregulation. The expression profile indicated that Nrf2 has a global influence on both MyD88-dependent and -independent signaling. Nrf2-deficient mouse embryonic fibroblasts showed greater activation of NF-kappaB and interferon regulatory factor 3 in response to LPS and polyinosinic-polycytidylic acid [poly(I:C)] stimulus, corroborating the effect of Nrf2 on MyD88-dependent and -independent signaling. Nrf2's regulation of cellular glutathione and other antioxidants is critical for optimal NF-kappaB activation in response to LPS and TNF-alpha. Our study reveals Nrf2 as a novel modifier gene of sepsis that determines survival by mounting an appropriate innate immune response.

MeSH Terms
Animals Antioxidants/pharmacology Cecum Cell Adhesion Molecules/metabolism Chemokines/metabolism Immunity, Innate/genetics Lipopolysaccharides Male Mice NF-E2-Related Factor 2/genetics,metabolism,physiology Pneumonia/immunology,metabolism Receptors, Cell Surface/metabolism Sepsis/immunology,metabolism Signal Transduction/immunology Transcription, Genetic Tumor Necrosis Factor-alpha/metabolism,pharmacology
Chemicals
Antioxidants Cell Adhesion Molecules Chemokines Lipopolysaccharides NF-E2-Related Factor 2 Receptors, Cell Surface Tumor Necrosis Factor-alpha
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Thimmulappa Rajesh K
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Lee Hannah
Rangasamy Tirumalai
Reddy Sekhar P
Yamamoto Masayuki
Kensler Thomas W
Biswal Shyam
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI25790
Published
2006-04-00
Pages
984-95
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1421348
Subset
IM
Grants
NIEHS NIH HHS · P30 ES 038819 · United States
NHLBI NIH HHS · R01 HL081205-03 · United States
NCI NIH HHS · R01 CA094076 · United States
NHLBI NIH HHS · R01 HL081205 · United States
NCI NIH HHS · P50 CA058184 · United States
NHLBI NIH HHS · HL081205 · United States
NHLBI NIH HHS · P50 HL073994 · United States
NCI NIH HHS · CA94076 · United States
NHLBI NIH HHS · R01 HL081205-02 · United States
Corrections
CommentIn
PMID: 16585954
External Links
PubMed source DOI: 10.1172/JCI25790 PMC Full Text View journal details
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