Can Activation of NRF2 Be a Strategy against COVID-19?
Authors: Antonio Cuadrado, Marta Pajares, Cristina Benito, José Jiménez-Villegas, Maribel Escoll, Raquel Fernández-Ginés, Angel J. Garcia Yagüe, Diego Lastra, Gina Manda, Ana I. Rojo, Albena T. Dinkova-Kostova
Journal: Trends in Pharmacological Sciences (2020)

The host inflammatory response is a crucial determinant of disease outcome and correlates with disease severity in SARS-CoV-2-induced infection, for which there is no treatment to date.Activation of transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) promotes resolution of inflammation and, in parallel, restores cellular redox and protein homeostasis, and facilitates tissue repair.NRF2 can be activated by pharmacological inducers that target Kelch-like ECH-associated protein 1 (KEAP1), the principal negative regulator of NRF2.The available information on pharmacokinetics, pharmacodynamics, safety, and efficacy for the NRF2 activators sulforaphane and bardoxolone methyl (currently in advanced clinical trials for other disease indications) in humans makes them excellent candidates for testing in randomized clinical trials in COVID-19. Acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 is largely the result of a dysregulated host response, followed by damage to alveolar cells and lung fibrosis. Exacerbated proinflammatory cytokines release (cytokine storm) and loss of T lymphocytes (leukopenia) characterize the most aggressive presentation. We propose that a multifaceted anti-inflammatory strategy based on pharmacological activation of nuclear factor erythroid 2 p45-related factor 2 (NRF2) can be deployed against the virus. The strategy provides robust cytoprotection by restoring redox and protein homeostasis, promoting resolution of inflammation, and facilitating repair. NRF2 activators such as sulforaphane and bardoxolone methyl are already in clinical trials. The safety and efficacy information of these modulators in humans, together with their well-documented cytoprotective and anti-inflammatory effects in preclinical models, highlight the potential of this armamentarium for deployment to the battlefield against COVID-19. Acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 is largely the result of a dysregulated host response, followed by damage to alveolar cells and lung fibrosis. Exacerbated proinflammatory cytokines release (cytokine storm) and loss of T lymphocytes (leukopenia) characterize the most aggressive presentation. We propose that a multifaceted anti-inflammatory strategy based on pharmacological activation of nuclear factor erythroid 2 p45-related factor 2 (NRF2) can be deployed against the virus. The strategy provides robust cytoprotection by restoring redox and protein homeostasis, promoting resolution of inflammation, and facilitating repair. NRF2 activators such as sulforaphane and bardoxolone methyl are already in clinical trials. The safety and efficacy information of these modulators in humans, together with their well-documented cytoprotective and anti-inflammatory effects in preclinical models, highlight the potential of this armamentarium for deployment to the battlefield against COVID-19. Numerous clinical observations during the outbreaks of coronaviruses – severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome-related coronavirus (MERS-CoV), and most recently SARS-CoV-2 – convincingly show that, in addition to virus propagation, the host inflammatory response is a crucial determinant of disease outcome [1.Guan W.J. et al.Clinical characteristics of coronavirus disease 2019 in China.N. Engl. J. Med. 2020; 382: 1861-1862Crossref PubMed Scopus (2383) Google Scholar]. A parallel can be drawn with influenza, for which lethality is not associated with the cytolytic action of the pathogen but instead with the inflammatory response orchestrated by the host immune system [2.Galani I.E. Andreakos E. Neutrophils in viral infections: current concepts and caveats.J. Leukoc. Biol. 2015; 98: 557-564Crossref PubMed Scopus (47) Google Scholar]. In the most severe cases of the disease, a cytokine storm (excess production of cytokines) [3.Huang C. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (4657) Google Scholar] is associated with T cell depletion, pulmonary inflammation, and lung damage. Patients showing acute respiratory distress syndrome (ARDS; see Glossary) and other types of virus-induced pneumonia also present features of macrophage activation syndrome (MAS) [3.Huang C. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (4657) Google Scholar]. There is also evidence of leukopenia, with a ~twofold decrease in T cell number [4.Qin C. et al.Dysregulation of immune response in patients with COVID-19 in Wuhan, China.Clin. Infect. Dis. 2020; (Published online March 12, 2020. https://doi.org/10.1093/cid/ciaa248)Crossref Google Scholar], which may be the result of pyroptosis, a form of cell death that mainly affects cells of the immune system [5.Fung S.Y. et al.A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses.Emerg. 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To comprehensively manage the symptoms of COVID-19 (the disease caused by SARS-CoV-2), it is crucial to understand the most appropriate context for introducing an anti-inflammatory therapy to complement an antiviral therapy. Such therapy must control inflammation without altering the ability of the host to mount an efficient adaptive immune response against the virus. We propose that boosting endogenous cellular defenses by targeting the cytoprotective transcription factor NRF2 (gene name NFE2L2) will promote the resolution of COVID-19 associated inflammation and also restore redox homeostasis and facilitate tissue repair. It should be noted that the protein under discussion is distinctly separate from the identically abbreviated nuclear respiratory factor 2 (also known as GA binding protein transcription factor subunit β, gene name GABPB1), a completely different transcription factor involved in mitochondrial biogenesis [8.Jornayvaz F.R. Shulman G.I. 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The role of NRF2 in viral infections has been investigated in the context of both DNA and RNA viruses. In general, viruses can benefit from either activating or inhibiting NRF2 in host cells [28.Deramaudt T.B. et al.Regulation of oxidative stress by Nrf2 in the pathophysiology of infectious diseases.Med. Mal. Infect. 2013; 43: 100-107Crossref PubMed Scopus (0) Google Scholar]. This might be dependent on factors such as the stage of infection [29.Wyler E. et al.Single-cell RNA-sequencing of herpes simplex virus 1-infected cells connects NRF2 activation to an antiviral program.Nat. 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Following infection with SARS-CoV, NF-κB is activated in lungs of mice and in human monocyte macrophages in vitro; conversely, inhibition of NF-κB decreases inflammation and improves survival after SARS-CoV infection in mice [7.DeDiego M.L. et al.Inhibition of NF-kappaB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival.J. Virol. 2014; 88: 913-924Crossref PubMed Scopus (0) Google Scholar,37.Dosch S.F. et al.SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro.Virus Res. 2009; 142: 19-27Crossref PubMed Scopus (33) Google Scholar]. Thus, pharmacological activation of NRF2 might also limit NF-κB-mediated inflammatory processes inflicted in the lung by SARS-CoV-2 infection. The SARS-CoV-2 genome encodes non-structural proteins (nsp) that are required for replication, structural proteins including spike (S), envelope (E), membrane (M), and nucleocapsid (N), and accessory proteins ORF3, 6, 7a, 7b, 8, and 9b that interact with the host cells [38.Zhu N. et al.A novel coronavirus from patients with pneumonia in China, 2019.N. Engl. J. Med. 2020; 382: 727-733Crossref PubMed Scopus (2517) Google Scholar]. The receptor-binding domain (RBD) located in the S protein of SARS-CoV-2 interacts with the angiotensin-converting enzyme 2 (ACE2) of host cells to allow viral entry (Figure 1) [39.Chen Y. et al.Structure analysis of the receptor binding of 2019-nCoV.Biochem. Biophys. Res. Commun. 2020; 525: 135-140Crossref PubMed Scopus (82) Google Scholar]. 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By analogy with other coronaviruses, SARS-CoV-2 is expected to modulate the host translational machinery to favor the generation of its own proteins (Figure 1) [44.Nakagawa K. et al.Viral and cellular mRNA translation in coronavirus-infected cells.Adv. Virus Res. 2016; 96: 165-192Crossref PubMed Scopus (11) Google Scholar]. Host countermeasures to this step include inactivation of eukaryotic initiation factor 2 (eIF2) by two of the three cellular eIF2α kinases, protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), which are known to be activated in response to SARS-CoV infection [45.Krahling V. et al.Severe acute respiratory syndrome coronavirus triggers apoptosis via protein kinase R but is resistant to its antiviral activity.J. Virol. 2009; 83: 2298-2309Crossref PubMed Scopus (35) Google Scholar]. 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Virol. 2017; 98: 2982-2992Crossref PubMed Scopus (2) Google Scholar], and this effect is phenocopied by the CO donor, CO-releasing molecule 2 (CORM-2), through a mechanism that depends on the activation of soluble guanylyl cyclase (sGC), which increases the local levels of cGMP and activates protein kinase G (PKG) (Figure 2). In turn, PKG inhibits NADPH oxidase (NOX) [67.Kalyanaraman H. et al.Protein kinase G activation reverses oxidative stress and restores osteoblast function and bone formation in male mice with type 1 diabetes.Diabetes. 2018; 67: 607-623Crossref PubMed Scopus (14) Google Scholar], preventing an increase in ROS levels (Figure 2) that otherwise would contribute to inflammation. If these mechanisms are also mirrored in the context of COVID-19, activation of the NRF2/HO-1 pathway holds promise for mitigating SARS-CoV-2 infection. An important limitation for the development of effective therapies against SARS-Cov-2 is the poor reproducibility of COVID-19 in animal models, most of which do not share relevant physiology, do