Signaling through the S1P−S1PR Axis in the Gut, the Immune and the Central Nervous System in Multiple Sclerosis: Implication for Pathogenesis and Treatment

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.

Sphingosine‐1‐phosphate receptor modulation improves neurogenesis and functional recovery after stroke

“…S1PRs consist of S1PR1–5 subtypes, among which S1PR1 is expressed in different types of SVZ cells, including neural stem and progenitor cells 14–16 . S1PR modulators can enter the brain and act on their receptors expressed by neuronal cell lineages, leading to modification of neuronal plasticity, myelination, and neuroprotection 17,18 . However, little is known about the potential impact of S1PR signaling on the activity of SVZ neural stem and progenitor cells.…”

The role of sphingosine-1-phosphate in the development and progression of Parkinson’s disease

“…Furthermore, S1P has anti-apoptotic and pro-growth effects among neural development and mediated by signaling from the S1P1 receptor ( Don-Doncow et al, 2019 ). The activation of S1PRs via S1P contributes to a serious of physiologic processes which involved in neuronal plasticity including myelination, neurogenesis and neuroprotection ( Chatzikonstantinou et al, 2021 ). S1P is more effective than fibroblast growth factor (FGF) in stimulating neurogenesis.…”

Targeting Chronic Inflammation of the Digestive System in Cancer Prevention: Modulators of the Bioactive Sphingolipid Sphingosine-1-Phosphate Pathway

“…S1PR1's ubiquitous expression on immune cells is associated with the stimulation of antiinflammatory responses and apoptosis in macrophages to trafficking of the dendritic and monocyte cells, the inhibition of IFN-α secretion, and the recruitment of eosinophils and mast cells, and is important in lymph node egress of the natural killer cells [67,68]. The functions of the S1PR2 complex include eosinophil and mast cell degranulation [70]. The S1PR3 complex is involved in the suppression of regulatory T-cells, promotion of Th1 response, and maturation of the dendritic cells, and is also involved in the trafficking of the monocytes and recruitment of the mast cells and eosinophils [67,71].…”