5.5. The nuclear Factor Erythroid 2-Related Factor 2 (NRF2)
NRF2, a transcription factor, upregulates the genes that are associated
with antioxidative stress and mitochondrial biogenesis. Cellular stress
activates NRF2 leading to its translocation to the nucleus, where it
binds to the antioxidant response element (ARE) to initiate the
transcription of antioxidant genes to protect cells against inflammatory
responses (Ahmed, Luo, Namani, Wang & Tang, 2017). NFR2 also has a gene
repressing activity that inhibits the transcription of cytokine genes,
resulting in a decrease in the expression of the inflammatory cytokines
IL-1β, IL-6, and TNF-α in human macrophages (Kobayashi et al., 2016). In
contrast, NRF2 knockout mice showed increased levels of proinflammatory
cytokines in response to lipopolysaccharide stimulation (Thimmulappa et
al., 2006a). In addition, NRF2 induces the expression of heme oxgenase-1
(HO-1) and increases the activity of HO-1 (Reichard, Motz & Puga,
2007). HO-1 functions to catalyze the degradation of heme into carbon
monoxide (CO), free iron, and biliverdin, which then is converted to
bilirubin by biliverdin reductase. Free heme is pro-inflammatory, while
CO, bilirubin, and HO-1 itself have significant anti-inflammatory
effects (Vijayan, Wagener & Immenschuh, 2018). CO can inhibit the
production of proinflammatory cytokines, such as TNF-α and IL-1β,
through mediating p38MPAK pathway (Otterbein et al., 2000). Increased
NRF2-dependent HO-1 expression has been associated with
anti-inflammatory activity (Kuhn et al., 2011). Moreover, NRF2 has been
shown to induce the quinone oxidoreductase (NQO1) expression and thereby
inhibit NLRP3 inflammasome activation (Liu et al., 2017). NRF2 also
inhibits NF-ĸB transcriptional activity, since NRF2 knockdown
significantly increases NF-ĸB-dependent gene transcription (Thimmulappa
et al., 2006b). The downstream target of NRF2, HO-1 can also inhibit
NF-ĸB activity (Bellezza et al., 2012). In response to oxidative stress,
activated IĸB kinase (IKK) promotes the phosphorylation and degradation
of IĸB. In normal condition, NF-ĸB is trapped in the cytoplasm by IĸB
binding. The loss of IĸB frees NF-ĸB, which is translocated to nucleus
to promote the gene transcription of pro-inflammatory cytokines, such as
IL-6, TNF-α, an IL-1 (Lawrence & Fong, 2010)(Figure 3).
As a result, proposed use of NRF2 inducers to prevent development of an
excessive inflammatory response in COVID-19 patients is rationale
(Zinovkin & Grebenchikov, 2020). Recently, NRF2 agonist
4-octyl-itaconate and dimethyl fumarate has been demonstrated to
attenuate inflammatory responses to SARS-CoV2 infection (Olagnier et
al., 2020). NRF2 agonists may be potentially valuable candidates in the
treatment of SARS-CoV-2 infection.