COVID-19 cytokine storm: The anger of inflammation

Abstract

Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.

Keywords: ACE2; COVID-19; Cytokine storm; SARS-CoV-2.

Fig. 1

SARS-CoV-2 driven ACE2 down-regulation leads to an array of complex and intertwined molecular interactions via at least four axes consisting of dysregulation of the ACE2/angiotensin II/AT1R axis, attenuation of ACE2/MasR axis, increased activation of ACE2/bradykinin B1R/DABK axis, and activation of the complement cascades, resulting to a tornado of inflammatory cytokine responses ,as described by Tisoncik et al. .

Fig. 2

ACE/Angiotensin II/AT1R and ACE2/MasR axis. The SARS-CoV-2 induced imbalance of ACE2/ACE that results in AT1R-mediated inflammatory response which will be accompanied with activation of the complement system, MAPK and NF-kB. The decrement of Ang (1–7) following SARS-CoV-2-mediated ACE2 down-regulation results in attenuation of MasR function. The MasR modulates AT1R-mediated inflammatory cytokine responses. Ang-(1–7) modulates the activity of ERK 1/2 via MasR. ERK 1/2 pathway induces production of IL-10, as an anti-inflammatory cytokine. Ang II, TLR2, TLR4, TLR9, and AP-1 transcription factor induce TGF-β expression. TGF-β has a role in the differentiation of T helper 17 cells from naive CD4+ T-cells.

Fig. 3

ACE2/Bradykinin B1R/DABK axis. Down-regulation of ACE2 by SARS-CoV-2 leads to increased activity of [des-Arg9]-BK (DABK) with resulting increased inflammatory cytokine responses. Safotibant is a promising drug to antagonize BKB1R.

Fig. 4

The complement system activation and its inhibitors. The complement system is activated through classical, lectin and alternative pathways. The nucleocapsid protein of SARS-CoV-2 results in aberrant production of C3 through MASP-2 mediated activation of mannose-binding lectin (MBL).