Endotoxemia rocks sphingolipid metabolism at the blood–brain barrier

Abstract

In this issue of the Journal of Neurochemistry, Vutukuri et al. evaluate the impact of endotoxemia-induced encephalopathy on the sphingosine-1-phosphate (S1P) signaling pathway at the blood-brain barrier (BBB). Four hours after intraperitoneal administration of lipopolysaccharides (LPS, 4 mg/kg) to mice, they first demonstrate BBB dysfunction and then evaluate changes in sphingolipid metabolites in serum, isolated brain microvessels (MBMV), and whole brain. In parallel, they investigate the fate of indicated S1P generating and metabolizing enzymes and S1P receptors in brain and MBMV. S1P levels decreased in serum and brain and a similar tendency was observed in MBMV. Sphk2 expression was strongly reduced in MBMV together with an up-regulation of lipid phosphate and S1P phosphatases, resulting in a net decrease in S1P levels despite a compensatory increase in Sphk1 expression. The implications of disturbed sphingolipid metabolism for the pathogenesis of septic encephalopathy will depend on the net impact of these changes on S1P receptor signaling at the BBB and the importance of the S1P pathway in regulating vascular homeostasis in this context.

Sphingosine kinase 1/S1P receptor signaling axis is essential for cellular uptake of Neisseria meningitidis in brain endothelial cells

“…The functional balance between signal transduction after activation of S1PR1/3 and S1PR2, respectively, at the BBB is well established, and confers to protection of barrier integrity via regulation of tight junction proteins or cytoskeletal rearrangement [22]. While plasma S1P levels are controlled systemically, it is possible that S1P levels at the BBB are controlled through local changes of S1P modulating enzymes and therefore S1P receptor signaling at the BBB could be controlled by endothelial cells in an autocrine manner by S1P release and S1P receptor expression [78,79]. Future studies are needed to determine the impact of S1P and S1PRs on the BBB disruption in response to N. meningitidis infection.…”