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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