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.