Persistent Activation of Sphingosine‐1‐Phosphate Receptor 1 by Phytosphingosine‐3,4‐Cyclic Phosphate Ameliorates Sepsis by Inhibiting Hyperinflammation and Vascular Hyperpermeability

ABSTRACT Sepsis is a life‐threatening disease characterized by multiorgan dysfunction caused by an abnormal immune response to microbial infection. Sphingosine‐1‐phosphate (S1P) levels are significantly lower in patients with sepsis and are negatively correlated with the severity of sepsis. However, whether the S1P signaling pathway is a target for sepsis treatment remains unknown. Here, we show that our newly synthesized phytosphingosine‐3,4‐cyclic phosphate (3,4‐cPP), a functional agonist of S1P receptor 1 (S1P1), exerts a strong protective effect against severe cecal ligation and puncture (CLP)‐induced sepsis. 3,4‐cPP persistently activates S1P1 without inducing internalization. 3,4‐cPP upregulates SIRT1 expression in macrophages and endothelial cells via S1P1 activation. Additionally, 3,4‐cPP decreases serum levels of proinflammatory cytokines, including IL‐6 and TNF‐α, and inhibits endothelial permeability in CLP‐induced septic mice. Conditional knockout of SIRT1, an NAD + ‐dependent deacetylase, in macrophages or endothelial cells counteracts the inhibition of inflammatory cytokine secretion and prevention of endothelial cell permeability by 3,4‐cPP in CLP‐induced septic mice, indicating that the S1P1/SIRT1 axis in both the endothelium and macrophages is essential for survival in sepsis. Collectively, the data suggest that prolonged activation of the S1P1/SIRT1 signaling pathway protects against sepsis by inhibiting hyperinflammation and vascular hyperpermeability.