An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation

Abstract

Inflammation is a key driver in many pathological conditions such as allergy, cancer, Alzheimer's disease, and many others, and the current state of available drugs prompted researchers to explore new therapeutic targets. In this context, accumulating evidence indicates that the transcription factor Nrf2 plays a pivotal role controlling the expression of antioxidant genes that ultimately exert anti-inflammatory functions. Nrf2 and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH- associated protein 1 (Keap1), play a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Interestingly, Nrf2 is proved to contribute to the regulation of the heme oxygenase-1 (HO-1) axis, which is a potent anti-inflammatory target. Recent studies showed a connection between the Nrf2/antioxidant response element (ARE) system and the expression of inflammatory mediators, NF-κB pathway and macrophage metabolism. This suggests a new strategy for designing chemical agents as modulators of Nrf2 dependent pathways to target the immune response. Therefore, the present review will examine the relationship between Nrf2 signaling and the inflammation as well as possible approaches for the therapeutic modulation of this pathway.

Keywords: Keap1; Nrf2; inflammation; oxidative stress; polyphenols.

Figure 1

A surface presentation of the Kelch domain (carton) with peptide from Neh2 domain of Nrf2 (sticks in mesh) from crystal structures: 2FLU.

Figure 2

Under normal homeostatic conditions, Keap1 homodimerizes through the N-terminal BTB domain and binds to the cullin-based (Cul3) E3 ligase, forming Keap1-Cul3-RBX1 (Ring box protein-1) E3 ligase complex, leading to Nrf2 ubiquitination and degradation. Under stress (electrophiles or ROS or endoplasmic reticulum (ER) stress) conditions, Nrf2 is released from Keap1-Cul3-RBX1 complex and translocates into the nucleus wherein it heterodimerizes with small Maf proteins (sMaf) and binds to the antioxidant response elements (AREs), leading to the transcription of ARE-driven genes.

Figure 3

Interplay of Nrf2/HO-1 axis and NF-κB in inflammation. Upon TLR signaling, NF-κB is liberated from IκB, by phosphorylation by the IKK complex. NF-κB then translocates into the nucleus and induces the expression of proinflammatory cytokines, CAMs and other molecules. Nrf2 induces increase in the cellular HO-1 expression and inhibits oxidative stress-mediated NF-κB activation and blocks the degradation of IκB-α. In addition, Nrf2 negatively regulates the IκB-α proteasomal degradation and nuclear translocation of NF-κB.