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Review
. 2017 Dec 20;18(12):2772.
doi: 10.3390/ijms18122772.

Nrf2, the Master Regulator of Anti-Oxidative Responses

Sandra Vomund  1 , Anne Schäfer  2 , Michael J Parnham  3 , Bernhard Brüne  4   5 , Andreas von Knethen  6   7
Affiliations
Review

Nrf2, the Master Regulator of Anti-Oxidative Responses

Sandra Vomund et al. Int J Mol Sci. .

Abstract

Tight regulation of inflammation is very important to guarantee a balanced immune response without developing chronic inflammation. One of the major mediators of the resolution of inflammation is the transcription factor: the nuclear factor erythroid 2-like 2 (Nrf2). Stabilized following oxidative stress, Nrf2 induces the expression of antioxidants as well as cytoprotective genes, which provoke an anti-inflammatory expression profile, and is crucial for the initiation of healing. In view of this fundamental modulatory role, it is clear that both hyper- or hypoactivation of Nrf2 contribute to the onset of chronic diseases. Understanding the tight regulation of Nrf2 expression/activation and its interaction with signaling pathways, known to affect inflammatory processes, will facilitate development of therapeutic approaches to prevent Nrf2 dysregulation and ameliorate chronic inflammatory diseases. We discuss in this review the principle mechanisms of Nrf2 regulation with a focus on inflammation and autophagy, extending the role of dysregulated Nrf2 to chronic diseases and tumor development.

Keywords: Nrf2; antioxidants; electrophiles; reactive oxygen species; transcription factor.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Regulation of Nrf2 expression. (A) Domain structure of Nrf2; (B) Keap1-dependent degradation of Nrf2 (mod. from [8]), T-bar = inhibition of Nrf2 degradation, consequently blocking Keap1 release; (C) Keap1-independent mechanism of Nrf2 degradation.
Figure 1
Figure 1
Regulation of Nrf2 expression. (A) Domain structure of Nrf2; (B) Keap1-dependent degradation of Nrf2 (mod. from [8]), T-bar = inhibition of Nrf2 degradation, consequently blocking Keap1 release; (C) Keap1-independent mechanism of Nrf2 degradation.
Figure 2
Figure 2
Positive feedback-loop of Nrf2 activation by p62/SQSTM1. (A) Domain structure of p62/SQSTM1; (B) p62/SQSTM1 is an important protein for selective autophagy, binds to Keap1 and other long-lived proteins and forms polyubiquitinated protein aggregates. Furthermore, it binds to the autophagy marker LC3 within the autophagosome, thereby leading the aggregated proteins into the autophagosome. After fusion with a lysosome, proteins and organelles, such as mitochondria, are degraded within the autophagosome. By binding to Keap1, p62/SQSTM1 stabilizes Nrf2 and enhances its translocation into the nucleus, where Nrf2 activates its target genes (↑ = upregulation of Nrf2 target genes). One of these genes is p62/SQSTM1.
Figure 3
Figure 3
Acetaminophen (APAP) metabolism within the liver. Entering hepatocytes, APAP is metabolized >80% by glucuronyltransferases and sulfotransferases to soluble conjugates, which are excreted into the urine. CYP P450 monooxygenases can metabolize APAP to the electrophilic reactive metabolite NAPQI that is detoxified by glutathione S-transferase (Gst) using glutathione (GSH). If GSH stocks are exhausted, NAPQI oxidizes liver proteins, especially mitochondrial proteins by covalent binding. This induces ROS generation and consequently oxidative stress, which can lead to hepatocyte necrosis and apoptosis. To counteract cell death, cytoprotective signaling via Nrf2 activation and stabilization is induced by oxidative stress. Thereby, Keap1 releases Nrf2 which translocates into the nucleus, induces cytoprotective gene expression and replenishes the GSH stores. APAP—acetaminophen; CYP—cytochrome P450; GSH—glutathione; Gst—glutathione S-transferase; mito—mitochondria; Keap1—Kelch-like ECH associated protein; NAPQI—N-acetyl-p-benzoquinone imine; Nrf2—NF-E2 p45-related factor 2; ROS—reactive oxygen species (adapted from [85]).
Figure 4
Figure 4
Influence of Nrf2 activation on COPD. Air pollutants, cigarette smoke and bacterial or viral infection cause oxidative stress and inflammation in the lung. Nrf2 activation induces cytoprotective gene expression to counteract the toxic effect of ROS. Moreover, Nrf2 inhibits transcription of proinflammatory cytokines, especially in macrophages, to reduce the recruitment of inflammatory cells into the lung. If Nrf2 is reduced, inflammation and ROS lead to cell death of lung epithelial cells and consequently mediate emphysema. CD4/CD8—effector/cytotoxic T-cells; IL—interleukins; —NF-E2 p45-related factor 2; ROS—reactive oxygen species, ↑/↓ = up-/downregulation of expression with a positive effect on disease progression, T-bars/T-bars = inhibition with a positive/negative effect on disease progression.
Figure 5
Figure 5
Roles of Nrf2 in tumorigenesis. Activated Nrf2 can prevent onset of cancer by protecting the cell from environmental stressors, like ROS and xenobiotics which can cause DNA damage. Low levels of Nrf2-target genes (reducing ROS levels and eliminating xenobiotics) can lead to tumorigenesis upon stress. In contrast, during tumor progression, Nrf2 activity can contribute to chemoresistance and the ability of tumor cells to circumvent apoptosis, whereas the inhibition of Nrf2 provokes cancer drug susceptibility and the loss of antiapoptotic signals.
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