Intricate relationship between SARS-CoV-2–induced shedding and cytokine storm generation: A signaling inflammatory pathway augmenting COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), through its ability to induce cytokine release syndrome, can set up a generalized inflammatory response together with activating multiple inflammatory pathways, which contributes to a dramatic increase in the number of mortalities and morbidities worldwide. Reportedly, the manipulative nature of coronavirus disease 2019 (COVID-19), which targets the immune system, often focuses on specific inflammation-related pathways, usually confined to interleukins and tumor necrosis factor-α (TNF-α), with a great emphasis on therapeutic approaches targeting the inhibition of these inflammatory mediators. The involvement of a disintegrin and metalloprotease 17 (ADAM-17) and matrix metalloproteinase-9 (MMP-9) in the pathogenesis of COVID-19, through their ability to potentiate the cytokine storm during an episode of SARS-CoV-2 infection, often goes unnoticed. In this review, the intricate relationship between ADAM-17 and MMP-9 together with angiotensin-converting enzyme 2 (ACE-2) as the main target for SARS-CoV-2 is highlighted in detail through a compilation of evidence-based literature; thus, we shed light on a proposed inflammatory pathway that COVID-19 may exploit to provoke an inflammatory response of a complex nature. Conclusively, our proposed mechanism acts as a means to developing a therapeutic approach aimed at modulating the intricate communication between ADAM-17 and MMP-9, where a great emphasis on the role of ACE-2 shedding and subsequent elevation in angiotensin II (Ang-II) levels is crucial to understanding the awry inflammatory response in patients with COVID-19. From this concept, designing a therapeutic strategy targeting multiple inflammatory mediators and enzymes simultaneously is another approach to unravel this global pandemic.

Inflammatory-Metal Profile as a Hallmark for COVID-19 Severity During Pregnancy

“…IP-10, which has been proposed as an early identifier of lung disease in COVID-19 patients ( Howe et al, 2021 ), was increased two-fold in the mild group and seven-fold in the severe group compared to controls. Interestingly, only TNF-α increased gradually as disease severity increased, as reported before ( Ben Moftah and Eswayah, 2022 ). On the other hand, lower circulating levels of IL-6, TNF-α, IL-α, and CCL4 were observed in the asymptomatic group of pregnant women with COVID-19 than healthy pregnant women.…”

The Correlation Between Immune Invasion and SARS-COV-2 Entry Protein ADAM17 in Cancer Patients by Bioinformatic Analysis

“…ADAM17 may be the master molecule involved in regulating IL-6 class switching, and through this, it can control inflammatory response to viral antigenic stimuli (53). We thus focus on analyzing the expressions of ADAM17 in normal heart tissues because the cytokine can easily increase the severity in younger people and eventually lead to death (54,55). The expressions in normal heart tissues of ADAM17 protein were medium, whereas those in normal heart tissues of ACE2 protein were under medium or lower, localizing in both membrane and cytoplasm.…”

Inflammatory pathways in COVID‐19: Mechanism and therapeutic interventions

“… 148 Ang II acts as a proinflammatory factor, inducing NF‐κB, deintegrin, and metalloproteinase 17 (ADAM17), which together promote TNF‐α, IL‐1β, MMP‐9, and epidermal growth factor receptor to act on inflammation and CS. 149 , 150 , 151 , 152 …”