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.

Keywords: Endothelial dysfunction; Endothelial permeability; SARS-CoV-2 infection; Sphingosine-1-phosphate; Sphingosine-1-phosphate receptor; Vascular inflammation.

Fig. 1

Pathway of sphingosine-1-phosphate (S1P). Sphingosine is converted by sphingosine kinase (Sphk1/2) to S1P, which leads to a cellular response through S1P receptors (S1PR1-5). Sphingosine lyase (S1PL) metabolises S1P to inactive metabolites

Fig. 2

Role of S1P in SARS-CoV-2 infection. S1P through S1PR1 induces transmembrane protease serine 2 (TMPRSS2), which activates the expression of ACE2, inducing the synthesis of S1P and activating sphingosine kinase1/2 (Sphk1/2)

Fig. 3

Role of S1P receptors in COVID-19. S1P via the activation of S1P receptor 1 (S1PR1), activates phosphoinositol 3 kinase (PI3K), which maintains vascular permeability and inhibits the development of endothelial dysfunction (ED). The activation of S1PR1 stimulates interferon alpha (INF-α) which inhibits viral infection and decreases viral load. This activation inhibits the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The activation of S1PR2 induces the release of pro-inflammatory cytokines (PIC) and the development of hyperinflammation. S1PR2 also triggers vascular permeability with the development of ED. Thus, the activation of S1PR2 increases the risk of development of ALI/ARDS