Interplay between Nrf2 and NF-κB in Neuroinflammatory Diseases

Abstract

Many neurodegenerative conditions involve redox imbalance and neuroinflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB) are key transcription factors regulating antioxidant and inflammatory pathways, respectively. These two opposing factors are inversely regulated, with activity of one most often accompanied by diminished activity of the other, giving rise to the oxidative stress and neuroinflammation evident in neurodegeneration. Emerging evidence is uncovering a complex interplay between Nrf2 and NF-κB, involving extensive interaction of regulatory mechanisms including cytosolic activators and repressors, transactivation partners and direct transcriptional crosstalk. Understanding these interactions may provide insight into the pathophysiology of neuroinflammatory diseases and facilitate discovery of novel therapeutic targets. Keywords Nrf2 Function and ActivationNrf2 is the master regulator of antioxidant pathways, responsible for promoting the transcription of hundreds of antioxidant and cytoprotective genes, and in the brain appears to be repressed in neurons and predominantly restricted to glia [1,2]. Nrf2 is a cap'n' collar basic leucine zipper transcription factor. Under normal conditions, Nrf2 is bound in the cytosol by its negative regulator Kelch-like ECHassociated protein (Keap1), a substrate adaptor protein of a Cullin3-dependent ubiquitin E3 ligase complex. Keap1 constitutively targets Nrf2 for proteasomal degradation. When activated, Nrf2 dissociates from Keap1 and can translocate to the nucleus where it forms heterodimers with small Maf proteins and binds to antioxidant response elements (AREs), promoting the transcription of a battery of antioxidant and cytoprotective genes [3]. Nrf2 targets include genes for glutathione synthesis and utilization (e.g. GCLM, GCLC, GSTs), the thioredoxin and peroxiredoxin systems, NAPDH generation, iron metabolism (HMOX1, FTL, FTH) and quinone detoxification (NQO1) [4]. Nrf2 can be activated in response to oxidative stress and electrophiles via Keap1. Keap1 contains several highly sensitive cysteine residues that when oxidised cause Nrf2 to dissociate from Keap1, allowing Nrf2 to translocate to the nucleus. Thus Keap1 acts as a redox sensor [3]. Nrf2 activity is also regulated by kinases such as GSK3β [5]. Regulation of NF-κB ActivationNF-κB is a key regulator of the cellular inflammatory profile, promoting the transcription of inflammatory genes. In the brain, NF-κB signalling occurs predominantly in microglia, as well as astrocytes and oligodendrocytes, but not in neurons [6]. The NF-κB complex consists of homo-or heterodimers of p65, RelB, c-Rel, p50 and p52, the most abundant of which is p65/p50. The dimers are bound in the cytosol by a family of repressor proteins called inhibitor of κB (IκB), which include IκBα, IκBβ, IκBε, IκBγ and Bcl-3. IκB is phosphorylated by the IκB kinase (IKK) complex, consisting of IKKα, IKKβ and IKKγ subunits [7]. Upon activation by stimuli including TNFα, LPS and IL-1, IKK phosph...

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