Cellular Localization of Sphingosine-1-phosphate Receptor 1 Expression in the Human Central Nervous System

Abstract

S U M M A R Y Sphingosine-1-phosphate (S1P), a potent lipid mediator, transduces intracellular signals through the activation of S1P receptors (S1PRs). Although S1PRs have been shown to play an important role in the central nervous system (CNS), accurate localization and the function of S1PR1 in the human CNS are still unclear. In this study, we investigated the localization of S1PR1 in the human CNS of postmortem samples, using a rabbit polyclonal antibody, the specificity of which had been well defined. Immunohistochemical investigation of paraffin-embedded sections revealed diffuse granular staining of the gray matter. The signals of the gray matter were much stronger than those of the white matter. The immunohistochemical expression levels correlated well with the results of quantitative real-time RT-PCR-based analysis and Western blotting. Studies using double immunostaining and immunoelectron microscopy revealed that the antigen was strongly expressed in the membrane of the astrocytic foot processes of glia limitans and astrocytes with radial cytoplasm, but not distributed in neurons. In neurological disorders, hypertrophic astrocytes with strong expression of glial fibrillary acidic protein exhibited significantly decreased expression of S1PR1 in contrast to its strong expression in astrocytes forming fibrillary gliosis. These results indicate that S1PR1 is localized in astrocytes, and its expression level may change during the processes that occur after brain damage. (J Histochem Cytochem 58:847-856, 2010)

Expression of LPP3 in Bergmann glia is required for proper cerebellar sphingosine‐1‐phosphate metabolism/signaling and development

“…S1P-mediated signaling regulates cell adhesion and/or cell shape in glial cells (Mullershausen et al 2007; Tas and Koschel 1998) and cerebellar astrocytic proliferation in vitro (Bassi et al 2006). Since LPP3 and S1P 1 are extremely abundant in BG (this work and Nishimura et al 2010), and that lack of LPP3 increases the availability of S1P and down-regulates S1P 1 in BG, it was possible that most of the abnormalities found in this cell type originated from altered S1P/S1P 1 metabolism/signaling. The similar changes in cell morphology and alterations in soma arrangement found in BG, in addition to the significant reduction in the expression of S1P 1 in our in vitro and in vivo pharmacological treatments with the S1P receptor modulator FTY720, strongly supports this hypothesis.…”

S1P1 Receptor Modulation with Cyclical Recovery from Lymphopenia Ameliorates Mouse Model of Multiple Sclerosis

“…S1P 1 -eGFP Expression in CNS. S1P 1 is thought to be expressed on several cell types involved in the pathogenesis of MS, including lymphocytes that invade and attack the CNS, endothelial cells that normally provide a barrier to entry of these lymphocytes into the CNS parenchyma (Cahalan et al, 2011), neurons that are targeted for destruction by autoreactive lymphocytes (Nishimura et al, 2010), and astrocytes, which play a major role in inflammation and CNS scarring associated with MS (Sorensen et al, 2003). We analyzed S1P 1 -eGFP protein expression on these different cell types through immunofluorescence assays using S1P 1 -eGFP mice, which retain full physiological and pharmacological functions from the native S1P 1 locus (Cahalan et al, 2011).…”

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

“…Although it was thought that myeloid cells were not affected significantly by FTY720 treatment (61), FTY720 has been shown to skew dendritic cell and macrophage responses towards anti-inflammatory profiles (28). Finally, the effect of FTY720 on other cell types in the CNS such as microglia which have been implicated in the pathogenesis of cerebral malaria (62) or astrocytes which are integral to BBB maintenance (63), and strongly express S1P receptors (64), cannot be excluded.…”