Protective role of ACE2 and its downregulation in SARS-CoV-2 infection leading to Macrophage Activation Syndrome: Therapeutic implications

Abstract

In light of the outbreak of the 2019 novel coronavirus disease (COVID-19), the international scientific community has joined forces to develop effective treatment strategies. The Angiotensin-Converting Enzyme (ACE) 2, is an essential receptor for cell fusion and engulfs the SARS coronavirus infections. ACE2 plays an important physiological role, practically in all the organs and systems. Also, ACE2 exerts protective functions in various models of pathologies with acute and chronic inflammation. While ACE2 downregulation by SARS-CoV-2 spike protein leads to an overactivation of Angiotensin (Ang) II/AT1R axis and the deleterious effects of Ang II may explain the multiorgan dysfunction seen in patients. Specifically, the role of Ang II leading to the appearance of Macrophage Activation Syndrome (MAS) and the cytokine storm in COVID-19 is discussed below. In this review, we summarized the latest research progress in the strategies of treatments that mainly focus on reducing the Ang II-induced deleterious effects rather than attenuating the virus replication.

Keywords: ACE2; COVID-19; Coronavirus; Macrophage Activation Syndrome (MAS); RAS system; SARS.

Graphical abstract

Fig. 1

Illustration of ACE2 Downregulation in COVID-19 patient and appearance of MAS. The virus enters the host cell by interacting with the ACE2 receptor through its spike protein. Later, the virus downregulates the ACE2 expression that in turn upregulates Ang II. Ang II is a product of the RAS system obtained by the cleavage of Ang I by enzyme ACE. The upregulated Ang II interacts with its receptor AT1R and modulates the gene expression of several inflammatory cytokines via NF-κB signaling. This Ang II/AT1R interaction also influences the macrophage activation that in turn produces the inflammatory cytokines Thereby, inducing ARDS or MAS. Also, some metalloproteases like ADAM17 shed these proinflammatory cytokines and ACE2 receptors to the soluble form which aids in loss of the protective function of surface ACE2 and may increase SARS pathogenesis. The treatment with Glucocorticoids, AT1R inhibitor, and All-trans retinoic acid tends to inhibit NF-κB signaling thus reducing the cytokine storms thereby improving the severity of SARS-CoV2 infection.

Fig. 2

Schematic representation of Angiotensin II effects. The interaction of Ang II with AT1R mediates the harmful effects leading to multi-organ failure.