Figure 2. Angiotensin II (Ang II) is involved in the diction of cytokine storm during SARS-CoV-2 infection. In the renin-angiotensin system, renin cleaves angiotensinogen into angiotensin I (Ang I), which is converted into Ang II by the angiotensin-converting enzyme (ACE). While ACE2 functions to converse Ang II to Angiotensin 1-7 (Ang 1-7). The binding of the S-protein of SARS‐CoV‐2 to ACE2 on the cell surface causes the downregulation of ACE2 expression, resulting in an increase in Ang II expression. Ang II binds to and activates Ang II receptor type 1 (AT1R) and Ang II receptor type 2 (AT2R). Activation of AT1R induces the release of cytokines and induction of inflammation, promotes fibrosis, and impairs redox balance, and induces vasoconstriction. In contrast, activation of AT2R leads to anti-inflammatory, anti-fibrotic, redox balance, and vasodilation. In addition, Ang II upregulates the expression of TLR4 and the downstream pathways. After activation, TLRs recruit cytoplasmic TIR domain-containing adaptor proteins such as myeloid differentiation primary-response 88 (MyD88) and TIR-containing adapter-inducing interferon-β (TRIF), leading to the activation of nuclear factor (NF)-κB, mitogen-activated protein kinases (MAPKs), or interferon-regulatory factor (IRF). Subsequently, the transcription of genes that are responsible for the synthesis and the release of proinflammatory cytokines are activated, promoting the release of cytokines and type I interferons (IFNs).
Figure 3. The role of nuclear factor erythroid 2-related factor 2 (NRF2) induced cell signaling. In response to oxidative stress, activated NRF2 represses the genes that are associated with the transcription of cytokine genes, resulting in a decrease in the expression of the inflammatory cytokines IL-1β, IL-6, and TNF-α. In addition, NRF2 induces the expression of heme oxygenase-1 (HO-1) and increases the activity of HO-1. 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. CO can inhibit the production of proinflammatory cytokines, such as TNF-α and IL-1β, through mediating p38MPAK pathway. Moreover, NRF2 can induce the expression of quinone oxidoreductase (NQO1) that inhibits NLRP3 inflammasome activation. In response to oxidative stress, activated IĸB kinase (IKK) promotes the phosphorylation of IĸB, resulting in the release and nuclear translocation of NF-ĸB, which then promote the gene transcription of pro-inflammatory cytokines, such as IL-6, TNF-α, and IL-1. NRF2 can inhibit NF-ĸB transcriptional activity directly or through activating HO-1.