The S1P₂ receptor regulates blood-brain barrier integrity and leukocyte extravasation with implications for...

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid which modulates vascular integrity through its receptors, S1P₁-S1P₅. Notably, S1P₂ has been shown to mediate the disruption of cerebrovascular integrity in vitro and in vivo. However, the mechanism underlying this process has not been fully elucidated. We evaluated the role of S1P₂ in blood-brain barrier (BBB) disruption induced by lipopolysaccharide (LPS)-mediated systemic inflammation and found that BBB disruption and neutrophil infiltration were significantly attenuated in S1pr2^-/- mice relative to S1pr2^+/- littermates. This is concomitant with attenuation of LPS-induced transcriptional activation of IL-6 and downregulation of occludin. Furthermore, S1pr2^-/- mice had significantly reduced expression of genes essential for neutrophil infiltration: Sele, Cxcl1, and Cxcl2. Conversely, pharmacological agonism of S1P₂ induced transcriptional activation of E-selectin in vitro and in vivo. Although S1P₂ does not appear to be required for activation of microglia, stimulation of microglial cells with the S1P₂ potentiated the response of endothelial cells to LPS. These results demonstrate that S1P₂ promotes LPS-induced neutrophil extravasation by inducing expression of endothelial adhesion molecule gene, Sele, and potentiating microglial inflammation of endothelial cells. It is likely that S1P₂ is a mediator of cerebrovascular inflammation and represents a potential therapeutic target for neurodegenerative disease such as vascular cognitive impairment.