Sphingosine 1 Phosphate at the Blood Brain Barrier: Can the Modulation of S1P Receptor 1 Influence the Response of Endothelial Cells and Astrocytes to Inflammatory Stimuli?

Abstract

The ability of the Blood Brain Barrier (BBB) to maintain proper barrier functions, keeping an optimal environment for central nervous system (CNS) activity and regulating leukocytes’ access, can be affected in CNS diseases. Endothelial cells and astrocytes are the principal BBB cellular constituents and their interaction is essential to maintain its function. Both endothelial cells and astrocytes express the receptors for the bioactive sphingolipid S1P. Fingolimod, an immune modulatory drug whose structure is similar to S1P, has been approved for treatment in multiple sclerosis (MS): fingolimod reduces the rate of MS relapses by preventing leukocyte egress from the lymph nodes. Here, we examined the ability of S1P and fingolimod to act on the BBB, using an in vitro co-culture model that allowed us to investigate the effects of S1P on endothelial cells, astrocytes, and interactions between the two. Acting selectively on endothelial cells, S1P receptor signaling reduced cell death induced by inflammatory cytokines. When acting on astrocytes, fingolimod treatment induced the release of a factor, granulocyte macrophage colony-stimulating factor (GM-CSF) that reduced the effects of cytokines on endothelium. In an in vitro BBB model incorporating shear stress, S1P receptor modulation reduced leukocyte migration across the endothelial barrier, indicating a novel mechanism that might contribute to fingolimod efficacy in MS treatment.

Cerebrospinal fluid NCAM levels are modulated by disease‐modifying therapies

“…24 But fingolimod does cross the blood-brain barrier (BBB) and acts on sphingosine-1-phosphate receptor 1, 3, and 5 in the CNS and may potentially influence the integrity of the BBB, neurons, and oligodendrocytes. 25 However, a few in vitro and in vivo studies show that the influence from fingolimod medication directly on cells in the CNS is limited. 26 The role of fingolimod in myelin repair is still controversial but in cuprizone and lysolecithin (LPC) demyelination animal models, fingolimod did not promote remyelination.…”

Fingolimod promotes blood–nerve barrier properties in vitro

“…As for endothelial cells, our previous study revealed direct BBB‐modulating effects which included the enhancement of the barrier properties of the BBB by upregulation of claudin‐5 expression and inhibition of the increase in VCAM‐1 levels in BMECs induced by MS sera (Nishihara et al., 2015). Other laboratories have also shown that S1P receptor signaling reduces the cell death resulting from inflammatory cytokines (Spampinato et al., 2015). These reports indicated that fingolimod directly affects endothelial cells which might contribute to its efficacy in the treatment of MS.…”

FTY720 Attenuates Retinal Inflammation and Protects Blood–Retinal Barrier in Diabetic Rats

“…BBB is regulated by S1PRs signaling, 64 and FTY720 can directly repair BBB under inflammatory conditions by up-regulation of claudin-5 and down-regulation of VCAM-1 in brain microvascular endothelial cells through modulation of S1P1. 65 However, it remains unknown whether FTY720 can protect BRB. We show that FTY720 can reduce retinal microvascular permeability and preserve BRB integrity.…”