Abstract
Sphingosine 1-phosphate (S1P) is a signaling molecule with complex biological functions that are exerted through the activation of sphingosine 1-phosphate receptors 1–5 (S1PR1–5). S1PR expression is necessary for cell proliferation, angiogenesis, neurogenesis and, importantly, for the egress of lymphocytes from secondary lymphoid organs. Since the inflammatory process is a key element of immune-mediated diseases, including multiple sclerosis (MS), S1PR modulators are currently used to ameliorate systemic immune responses. The ubiquitous expression of S1PRs by immune, intestinal and neural cells has significant implications for the regulation of the gut–brain axis. The dysfunction of this bidirectional communication system may be a significant factor contributing to MS pathogenesis, since an impaired intestinal barrier could lead to interaction between immune cells and microbiota with a potential to initiate abnormal local and systemic immune responses towards the central nervous system (CNS). It appears that the secondary mechanisms of S1PR modulators affecting the gut immune system, the intestinal barrier and directly the CNS, are coordinated to promote therapeutic effects. The scope of this review is to focus on S1P−S1PR functions in the cells of the CNS, the gut and the immune system with particular emphasis on the immunologic effects of S1PR modulation and its implication in MS.
Highlights
Sphingolipids, including sphingomyelin and its metabolites, are structural components of all cell membranes and of the myelin sheath in the nervous system
In vitro models of astrocytes generated from human fibroblasts and on spinal neurons exposed to astrocyte-conditioned media have described that, siponimod targeting of sphingosine 1-phosphate (S1P) receptors resulted in the inhibition of NFκB translocation and enhancement of nuclear translocation of Nrf2
Ozanimod has been shown to exert neuroprotective actions, via S1PR1 binding, in EAE brain specimens and microglial cell cultures, by promoting amelioration of EAE-driven striatal glutamatergic synapse alterations [134]. These findings indicate that S1PR modulators may target the neurodegenerative component of the disease along with the inflammatory one
Summary
Sphingolipids, including sphingomyelin and its metabolites, are structural components of all cell membranes and of the myelin sheath in the nervous system. Interacts with intracellular targets or paracrine cell targets, to activate the G-protein-coupled receptor named sphingosine 1is transported extracellularly by ABC transporters, in autocrine or paracrine cell targets, phosphate receptors 1–5 (S1PRs 1–5) (Figure 1). S1P from degrasuppresses cytokine-induced inflammatory responses in endothelial cells, maintaining dation and integrity enhances interaction with receptors [11]. Diverse cellular suppresses cytokine-induced inflammatory responses in endothelial cells, maintaining vascular integrity [11,12]. S1PRs are ubiquitously expressed in the body, including by immune, cardiovascular, intestinal and neural cells [13] Cells 2021, 10, 3217 functions via intracellular signaling cascades, coupling with different G-proteins like Gi, Gq, Go, G12/13 and Rho that activate adenylyl cyclase, PLC, phospholipases D (PLD), ERK, Akt, PI3K, c-Jun N-terminal kinase (JNK), p38 MAPK and non-receptor tyrosine kinases. S1PR4 and S1PR5 are less numerous and less widely expressed, mainly by lymphatic and nervous cells [11,14]
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