Targeting pivotal inflammatory pathways in COVID-19: A mechanistic review

Abstract

As an emerging global health crisis, coronavirus disease 2019 (COVID-19) has been labeled a worldwide pandemic. Growing evidence is revealing further pathophysiological mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Amongst these dysregulated pathways inflammation seems to play a more critical role toward COVID-19 complications. In the present study, precise inflammatory pathways triggered by SARS-CoV-2, along with potential therapeutic candidates have been discussed. Prevailing evidence has indicated a close correlation of inflammatory cascades with severity, pathological progression, and organ damages in COVID-19 patients. From the mechanistic point of view, interleukin-6, interleukin-1β receptor, interferon-gamma, tumor necrosis factor-alpha receptor, toll-like receptor, receptor tyrosine kinases, growth factor receptor, Janus kinase/signal transducers and transcription pathway, mammalian target of rapamycin, cytokine storm and macrophage activation have shown to play critical roles in COVID-19 complications. So, there is an urgent need to provide novel mechanistic-based anti-inflammatory agents. This review highlights inflammatory signaling pathways of SARS-CoV-2. Several therapeutic targets and treatment strategies have also been provided in an attempt to tackle COVID-19 complications.

To stress or not to stress: Brain-behavior-immune interaction may weaken or promote the immune response to SARS-CoV-2

“…Acute, short-term psychosocial stress can also mobilize endogenous factors such as secreted Ly-6/uPAR related protein-1 (SLURP1) that neutralize the infection-promoting effects of nicotine on its receptors by stabilizing barrier function and promoting T-cell activation ( Campbell et al, 2019 ; Peters et al, 2014 M; Razani-Boroujerdi et al, 2004 ; Tjiu et al, 2011 ). Finally, acute psychosocial stress leads to the rapid but transient release of neuropeptides such as SP from peripheral nerve endings in mucosae and skin, and this may contribute to first-line anti-viral defense by short-term upregulation of toll-like receptors (TLRs) ( Larsson et al, 2018 ; Yarmohammadi et al, 2021 ).…”

Targeting Neurological Manifestations of Coronaviruses by Candidate Phytochemicals: A Mechanistic Approach

“…It also inhibits neuroapoptosis by reducing FGF-2 and suppressing NF-κB ( Xu et al, 2018 ). Considering the critical role of the aforementioned inflammatory mediators in COVID-19 ( Yarmohammadi et al, 2020 ), resveratrol could potentially decline neuroinflammatory signs of COVID-19 patients ( Chen et al, 2005 ). As a major natural derivative of resveratrol, polydatin potentially decline the neural levels of NF-κB, TNF-α, IL-1β, IL-6, IL-8, prostaglandin E2 (PGE2), NO, COX-2, iNOS, matrix metalloproteinase (MMP)-3 and MMP-9, thereby could be a novel agents in combating neuronal inflammatory manifestation in COVID-19 ( Lo Muzio et al, 2020 ).…”

“…As a critical sign of COVID-19, neuroinflammation occurs through elevated levels of neuronal interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), granulocyte colony-stimulating factor (GMCSF), IFN-γ-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein 1α (MIP1α), and T cell expression ( Xu et al, 2005 ; Yarmohammadi et al, 2020 ). The coronaviruses release inflammatory mediators to stimulate macrophages.…”

Altered Transcript Levels of Cytokines in COVID-19 Patients

“…A number of recent investigations have demonstrated elevated levels of pro-in ammatory cytokines in the critically ill COVID-19 patients compared with moderately ill ones (3,4). Induction of immune responses during the course of COVID-19 has been shown to result in the overproduction of enormous quantities of in ammatory proteins, eventually leading to organ damage (5). Up-regulation of pro-in ammatory cytokines such as IL-6, IL-1β, IL-18, and TNF-α in addition to their downstream molecules have been reported in these patients (6,7).…”

“…Moreover, dysregulation of a number of other in ammatory molecules such as IL-2, IL-7, IL-10 and IFN-γ have been associated with COVID-19 (8). Totally, many studies have shown the important impact of IL-6, IFN-γ and TNF-α in the pathobiology of this condition and related organ damage (5). Thus, identi cation of these in ammatory reactions has signi cance in the treatment of patients with COVID-19 infection (9).…”