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Review
. 2014 Apr:79:298-306.
doi: 10.1016/j.neuropharm.2013.11.004. Epub 2013 Nov 19.

NRF2-regulation in brain health and disease: implication of cerebral inflammation

Mats Sandberg  1 , Jaspal Patil  1 , Barbara D'Angelo  2 , Stephen G Weber  3 , Carina Mallard  4
Affiliations
Review

NRF2-regulation in brain health and disease: implication of cerebral inflammation

Mats Sandberg et al. Neuropharmacology. 2014 Apr.

Abstract

The nuclear factor erythroid 2 related factor 2 (NRF2) is a key regulator of endogenous inducible defense systems in the body. Under physiological conditions NRF2 is mainly located in the cytoplasm. However, in response to oxidative stress, NRF2 translocates to the nucleus and binds to specific DNA sites termed "anti-oxidant response elements" or "electrophile response elements" to initiate transcription of cytoprotective genes. Acute oxidative stress to the brain, such as stroke and traumatic brain injury is increased in animals that are deficient in NRF2. Insufficient NRF2 activation in humans has been linked to chronic diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. New findings have also linked activation of the NRF2 system to anti-inflammatory effects via interactions with NF-κB. Here we review literature on cellular mechanisms of NRF2 regulation, how to maintain and restore NRF2 function and the relationship between NRF2 regulation and brain damage. We bring forward the hypothesis that inflammation via prolonged activation of key kinases (p38 and GSK-3β) and activation of histone deacetylases gives rise to dysregulation of the NRF2 system in the brain, which contributes to oxidative stress and injury.

Keywords: Anti-oxidants; NRF2; Neuroinflammation.

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Figures

Figure 1
Figure 1. Regulation of NRF2 activation following acute (A) and prolonged (B) inflammation
(A) Based on our studies (45, 85, 86, 90) we suggest that acute inflammation can oxidize/modify certain thiols in the KEAP1 dimer and activate kinases such as AKT, ERK and JNK. This will lead to that NRF2 escapes from being ubiquinated by Cullin-3 (Cul3) and then transported to the nucleus, a process that is promoted by phosphorylation. Inside the nucleus, NRF2 combines with proteins such as MAFs. The complex binds to certain DNA motifs in promoters, so called anti-oxidant response elements (ARE), of hundreds of protective genes. The NRF2-mediated transcription is enhanced by acetylation of histones (H3/4). The effect of acute inflammation on NRF2 activation is reduced oxidative stress by elevated levels of cytoprotective proteins and anti-oxidants such as glutathione, creating a cellular environment that will reduce inflammation. For a more complete description of established (solid arrows) and putative (dashed arrows) kinases involved in NRF2 activation during acute inflammation see main text. (B) Prolonged neuroinflammation, i.e. overactivation of microglia and elevated levels of proinflammatory cytokines, leads to sustained activation of GSK-3β and p38 (45, 85, 86, 90). We propose that the activation of GSK-3β and p38 leads to phosphorylation of NRF2 at sites that enhance the binding to KEAP1, which will elevate the ubiquitination of NRF2 and thereby enhance degradation. GSK-3β can also phosphorylate FYN, which is transported to the nucleus. Inside the nucleus phosphorylation of NRF2 by FYN will lead to export of NRF2 out of the nucleus. Intranuclear KEAP1 can compete with binding of NRF2 to ARE, and the complex NRF2-KEAP1 can be exported to the cytosol where NRF2 is degraded. Further, decreased histone acetylation caused by elevated HDAC activity will reduce NRF2 mediated transcription. The increase in HDAC activity can be partly caused by the prolonged activation of GSK-3β and p38. The inactivation of the NRF2 system will lead to sustained and elevated activation of microglia and increased vulnerability to oxidative stress. Note the key importance of activation of AKT as a mean to reduce GSK-3β activation. For a more complete description of established (solid arrows) and putative (dashed arrows) kinases involved in NRF2 activation during prolonged inflammation see main text.
Figure 1
Figure 1. Regulation of NRF2 activation following acute (A) and prolonged (B) inflammation
(A) Based on our studies (45, 85, 86, 90) we suggest that acute inflammation can oxidize/modify certain thiols in the KEAP1 dimer and activate kinases such as AKT, ERK and JNK. This will lead to that NRF2 escapes from being ubiquinated by Cullin-3 (Cul3) and then transported to the nucleus, a process that is promoted by phosphorylation. Inside the nucleus, NRF2 combines with proteins such as MAFs. The complex binds to certain DNA motifs in promoters, so called anti-oxidant response elements (ARE), of hundreds of protective genes. The NRF2-mediated transcription is enhanced by acetylation of histones (H3/4). The effect of acute inflammation on NRF2 activation is reduced oxidative stress by elevated levels of cytoprotective proteins and anti-oxidants such as glutathione, creating a cellular environment that will reduce inflammation. For a more complete description of established (solid arrows) and putative (dashed arrows) kinases involved in NRF2 activation during acute inflammation see main text. (B) Prolonged neuroinflammation, i.e. overactivation of microglia and elevated levels of proinflammatory cytokines, leads to sustained activation of GSK-3β and p38 (45, 85, 86, 90). We propose that the activation of GSK-3β and p38 leads to phosphorylation of NRF2 at sites that enhance the binding to KEAP1, which will elevate the ubiquitination of NRF2 and thereby enhance degradation. GSK-3β can also phosphorylate FYN, which is transported to the nucleus. Inside the nucleus phosphorylation of NRF2 by FYN will lead to export of NRF2 out of the nucleus. Intranuclear KEAP1 can compete with binding of NRF2 to ARE, and the complex NRF2-KEAP1 can be exported to the cytosol where NRF2 is degraded. Further, decreased histone acetylation caused by elevated HDAC activity will reduce NRF2 mediated transcription. The increase in HDAC activity can be partly caused by the prolonged activation of GSK-3β and p38. The inactivation of the NRF2 system will lead to sustained and elevated activation of microglia and increased vulnerability to oxidative stress. Note the key importance of activation of AKT as a mean to reduce GSK-3β activation. For a more complete description of established (solid arrows) and putative (dashed arrows) kinases involved in NRF2 activation during prolonged inflammation see main text.
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