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.