Receptor-dependent effects of sphingosine-1-phosphate (S1P) in COVID-19: the black side of the moon

Abstract

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection leads to hyper-inflammation and amplified immune response in severe cases that may progress to cytokine storm and multi-organ injuries like acute respiratory distress syndrome and acute lung injury. In addition to pro-inflammatory cytokines, different mediators are involved in SARS-CoV-2 pathogenesis and infection, such as sphingosine-1-phosphate (S1P). S1P is a bioactive lipid found at a high level in plasma, and it is synthesized from sphingomyelin by the action of sphingosine kinase. It is involved in inflammation, immunity, angiogenesis, vascular permeability, and lymphocyte trafficking through G-protein coupled S1P receptors. Reduction of the circulating S1P level correlates with COVID-19 severity. S1P binding to sphingosine-1-phosphate receptor 1 (S1PR1) elicits endothelial protection and anti-inflammatory effects during SARS-CoV-2 infection, by limiting excessive INF-α response and hindering mitogen-activated protein kinase and nuclear factor kappa B action. However, binding to S1PR2 opposes the effect of S1PR1 with vascular inflammation, endothelial permeability, and dysfunction as the concomitant outcome. This binding also promotes nod-like receptor pyrin 3 (NLRP3) inflammasome activation, causing liver inflammation and fibrogenesis. Thus, higher expression of macrophage S1PR2 contributes to the activation of the NLRP3 inflammasome and the release of pro-inflammatory cytokines. In conclusion, S1PR1 agonists and S1PR2 antagonists might effectively manage COVID-19 and its severe effects. Further studies are recommended to elucidate the potential conflict in the effects of S1P in COVID-19.

Mixed storm in SARS‐CoV‐2 infection: A narrative review and new term in the Covid‐19 era

“… 2 , 40 Sudden uncontrolled release of proinflammatory cytokines and chemokines is the most suitable definition for CS. 35 , 39 , 41 …”

“…2,40 Sudden uncontrolled release of proinflammatory cytokines and chemokines is the most suitable definition for CS. 35,39,41 The potential mechanism of CS in SARS-CoV-2 infection is complex and related to intricate interaction between SARS-CoV-2 and immune cells. 8,42 During SARS-CoV-2 infection and associated cytopathic injury, PAMPs are released which activate PRRs.…”

“…Notably, hypercytokinemia which is a different entity from that of CS refers to the increasing levels of proinflammatory cytokines in different infectious and inflammatory disorders 2,40 . Sudden uncontrolled release of proinflammatory cytokines and chemokines is the most suitable definition for CS 35,39,41 …”

SARS‐CoV‐2 induced HDL dysfunction may affect the host's response to and recovery from COVID‐19

“…The anti‐inflammatory effect of HDL is through receptors‐dependent mechanisms. HDL activates scavenger receptor B1 (SR‐B1) and sphingosine‐phosphate receptor (S1P), causing the release of endothelial nitric oxide (NO) 28 . This change by HDL reduces endothelial permeability, expression of adhesion molecules, and inhibition of inflammatory signaling pathways, including nuclear factor kappa B (NF‐κB) 29 .…”

The possible role of nuclear factor erythroid‐2‐related factor 2 activators in the management of Covid‐19

“…[13][14][15] Covid-19 hypercoagulability may be caused by the prothrombotic effects of increased Ang II. [16][17][18][19] The COVID-19associated vasculopathy may be facilitated by the upregulation of ACE/Ang II and downregulation of ACE2/Ang-(1-7) in the vascular endothelium. [186] In the context of insulin resistance, earlier investigations have shown a connection between the Renin-Angiotensin-Aldosterone system (RAAS) and ER stress.…”