Commentary - Journal of Cellular Signaling (2021) Volume 2, Issue 2
Ectodomain Shedding May Play a Pivotal Role in Disease Severity in COVID-19
Rui Yamaguchi, Yasuo Yamaguchi*
Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325 Kumamoto 861-5598, Japan
- *Corresponding Author:
- Yasuo Yamaguchi
Received date: April 16, 2021; Accepted date: May 21, 2021
Citation: Yamaguchi R, Yamaguchi Y. Ectodomain Shedding May Play a Pivotal Role in Disease Severity in COVID-19. J Cell Signal 2021; 2(2): 100-102.
Copyright: © 2021 Yamaguchi R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Ectodomain shedding mediated by a disintegrin and metalloprotease 10/17 (ADAM10/17) modulates the function of immune effector cells and may be involved in the novel coronavirus disease COVID-19. Toll-like receptor 7/8 (TLR7/8) recognizes single-strand RNA from viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, the virus that causes COVID-19) during the innate immune response , and TLR7/8 agonist activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate reactive oxygen species (ROS) . ADAM10/7 was found to mediate ectodomain shedding to modulate immune responses  and to be activated by ROS . These findings suggest that SARS-CoV-2 contributes to and induces ectodomain shedding, which may be associated with disease severity. In patients with COVID-19, studies found a higher blood concentration of the chemokine fractalkine . Cell membrane-bound angiotensin-converting enzyme 2 (ACE2) has been identified as a binding site and entry receptor for the spike protein of SARS-CoV-2. After the virus binds to ACE2, ACE2 is internalized; ACE2 shedding also is mediated and enhanced by ADAM10/17 [6,7]. ACE2 deficiency increases expression of fractalkine [5,8]. ACE2 catalyzes and degrades angiotensin II, leading to the production of angiotensin 1-7, which binds to the angiotensin 1-7 (MAS) receptor and acts as a vasodilator (Figure 1). Indeed, binding of SARS-CoV-2 to ACE2 leads to ACE2 deficiency, which potentiates angiotensin II activity. Excess angiotensin II then activates NF-κB through the angiotensin type 1 receptor (AT1) and type 2 receptor (AT2) signaling pathway to enhance cytokine production (Figure 2). This mechanism explains how COVID-19 induces a cytokine storm . Most importantly, angiotensin II activates NADPH oxidase to generate ROS , ie, superoxide (O2-) and hydrogen peroxide (H2O2). In cells stimulated with interleukin-1β (IL-1β), the angiotensin II/AT1 and AT2 axis augments expression of inducible nitric oxide synthase (iNOS) to generate nitric oxide (NO) ; NO reacts with the peroxidase domain of the enzyme dual oxidase 2, which has both a peroxidase domain and an NADPH oxidase domain, to produce the strong biological oxidant agent peroxynitrite (ONOO-). Both H2O2 and ONOO- contribute to enhanced activation of ectodomain shedding by ADAM10/17. The fractalkine receptor CX3CR1 is highly expressed by macrophages, and soluble fractalkine shed from cells because of cleavage by ADAM10/17 activates macrophages to cause a hyperinflammatory response. SARS-CoV-2 also induces cytotoxic CD8+ T cells to produce perforin and granzyme B, which show aberrant hyperactivation and target cell killing . CX3CR1 is expressed by these cytotoxic CD8+ T cells, and fractalkine acts as a chemoattractant for them. Taken together, these findings indicate that ectodomain shedding may be closely associated with severity of COVID-19.
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