Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis
Rajesh K. Thimmulappa, Hannah Lee, Tirumalai Rangasamy, Sekhar P. Reddy, Masayuki Yamamoto, Thomas W. Kensler, Shyam Biswal
Rajesh K. Thimmulappa, Hannah Lee, Tirumalai Rangasamy, Sekhar P. Reddy, Masayuki Yamamoto, Thomas W. Kensler, Shyam Biswal
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Research Article

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

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-α 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-κB 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-κB activation in response to LPS and TNF-α. Our study reveals Nrf2 as a novel modifier gene of sepsis that determines survival by mounting an appropriate innate immune response.

Authors

Rajesh K. Thimmulappa, Hannah Lee, Tirumalai Rangasamy, Sekhar P. Reddy, Masayuki Yamamoto, Thomas W. Kensler, Shyam Biswal

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Figure 4

Greater expression of proinflammatory genes associated with the innate immune response in the lungs of Nrf2-deficient mice.

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Greater expression of proinflammatory genes associated with the innate i...
(A–C) Expression of cytokines (A), chemokines (B), and adhesion molecules/receptors (C) 30 minutes after nonlethal i.p. injection of LPS (60 μg per mouse) in Nrf2-deficient and wild-type mice. Gene expression data were obtained from microarray analysis. Data are represented as mean fold change obtained from comparing LPS-challenged to vehicle-treated lungs of the same genotype on a semilog scale. All the represented fold change values of LPS-treated lungs of Nrf2–/– mice are significant compared with wild-type mice at P <0.05.