Secrets and lyase: Control of sphingosine 1‐phosphate distribution

Dixit, Dhaval; Okuniewska, Martyna; Schwab, Susan R.

doi:10.1111/imr.12760

Cited by 24 publications

(14 citation statements)

References 126 publications

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“…In lung-transplanted CF patients, plasma levels of unbound S1P were lower than control subjects, and relevant differences were measured depending on the genotype of CF patients [ 10 ]. S1P concentration is normally elevated in blood and lymph, and low in tissues [ 39 , 40 ]. This gradient is finely tuned by a complex equilibrium between synthesizing and catabolizing enzymes, together with transporter proteins that regulate S1P passage across the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells

et al. 2021

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The role of S1P in Cystic Fibrosis (CF) has been investigated since 2001, when it was first described that the CFTR channel regulates the inward transport of S1P. From then on, various studies have associated F508del CFTR, the most frequent mutation in CF patients, with altered S1P expression in tissue and plasma. We found that human bronchial epithelial immortalized and primary cells from CF patients express more S1P than the control cells, as evidenced by mass spectrometry analysis. S1P accumulation relies on two- to four-fold transcriptional up-regulation of SphK1 and simultaneous halving of SGPL1 in CF vs. control cells. The reduction of SGPL1 transcription protects S1P from irreversible degradation, but the excessive accumulation is partially prevented by the action of the two phosphatases that are up-regulated compared to control cells. For the first time in CF, we describe that Spns2, a non-ATP dependent transporter that normally extrudes S1P out of the cells, shows deficient transcriptional and protein expression, thus impairing S1P accrual dissipation. The in vitro data on CF human bronchial epithelia correlates with the impaired expression of Spns2 observed in CF human lung biopsies compared to healthy control.

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Section: Discussionmentioning

confidence: 99%

Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells

et al. 2021

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“…Downregulation of the S1P Transporter Spns2, which is known to export S1P and thereby reduces intracellular S1P, abolishes the strong induction of MCP‐1 by TNF‐α and IL‐1β in the human renal proximal tubular epithelial cells [37]. S1P mainly acts through five high affinity G protein‐coupled S1P receptors, which are ubiquitously expressed and mediate a complex network of signaling in a cell type dependent manner [38, 39]. In fact, our previous study has demonstrated that S1P leads to the up‐regulation of MCP‐1 mRNA and protein via S1P receptor 2 and 3 in BMMs [6].…”

Section: Discussionmentioning

confidence: 99%

Sphingosine 1‐phosphate/microRNA‐1249‐5p/MCP‐1 axis is involved in macrophage‐associated inflammation in fatty liver injury in mice

Yang

Zhang

et al. 2020

Eur J Immunol

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Monocyte chemotactic protein‐1 (MCP‐1) is one of the most representative inflammatory cytokines, and has been proved to be markedly increased in injured liver and sphingosine 1‐phosphate (S1P)‐treated macrophages. However, microRNAs (miRNAs) targeting MCP‐1 and the role of miRNA/MCP‐1 axis in S1P‐mediated liver inflammation remain largely unknown. Here, we demonstrate that MCP‐1 expression is increased in the liver and isolated liver macrophages of MCDHF mice. Moreover, there is a positive correlation between the hepatic levels of S1P and MCP‐1. We then predict miRNAs targeting MCP‐1 by bioinformatics analysis and select miRNA‐1249‐5p (miR‐1249‐5p) from the intersection of TargetScan database and downregulated miRNAs in the injured liver. S1P significantly upregulates the expression of MCP‐1 and decreases miR‐1249‐5p expression in macrophages. MiR‐1249‐5p directly targets 3’‐UTR of MCP‐1 and negatively regulates its expression in S1P‐treated macrophages. Administration of miR‐1249‐5p agomir decreases hepatic MCP‐1 levels and attenuates liver inflammation in MCDHF mice. Protein‐protein interaction network by STRING displays that S1P system is closely associated with MCP‐1/CCR2 axis in the network of inflammation. In conclusion, we characterize the vital role of miR‐1249‐5p in negatively regulating MCP‐1 expression in vitro and in vivo, which may open new perspectives for pharmacological treatment of liver disease.

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“…Sphingosine 1-phosphate (S1P), a product of cell membrane sphingolipid catabolism, is a pleiotropic mediator involved in a variety of cellular functions such as adhesion, migration, inflammation, and proliferation in many cell types (7)(8)(9). S1P is generated from sphingosine intracellularly by sphingosine kinases 1 and 2 (SphK1 and SphK2).…”

Section: Introductionmentioning

confidence: 99%

Sphingosine 1-phosphate signaling in perivascular cells enhances inflammation and fibrosis in the kidney

et al. 2022

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Chronic kidney disease (CKD), characterized by sustained inflammation and progressive fibrosis, is highly prevalent and can eventually progress to end-stage kidney disease. However, current treatments to slow CKD progression are limited. Sphingosine 1-phosphate (S1P), a product of sphingolipid catabolism, is a pleiotropic mediator involved in many cellular functions, and drugs targeting S1P signaling have previously been studied particularly for autoimmune diseases. The primary mechanism of most of these drugs is functional antagonism of S1P receptor-1 (S1P1) expressed on lymphocytes and the resultant immunosuppressive effect. Here, we documented the role of local S1P signaling in perivascular cells in the progression of kidney fibrosis using primary kidney perivascular cells and several conditional mouse models. S1P was predominantly produced by sphingosine kinase 2 in kidney perivascular cells and exported via spinster homolog 2 (Spns2). It bound to S1P1 expressed in perivascular cells to enhance production of proinflammatory cytokines/chemokines upon injury, leading to immune cell infiltration and subsequent fibrosis. A small-molecule Spns2 inhibitor blocked S1P transport, resulting in suppression of inflammatory signaling in human and mouse kidney perivascular cells in vitro and amelioration of kidney fibrosis in mice. Our study provides insight into the regulation of inflammation and fibrosis by S1P and demonstrates the potential of Spns2 inhibition as a treatment for CKD and potentially other inflammatory and fibrotic diseases that avoids the adverse events associated with systemic modulation of S1P receptors.

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Secrets and lyase: Control of sphingosine 1‐phosphate distribution

Cited by 24 publications

References 126 publications

Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells

Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells

Sphingosine 1‐phosphate/microRNA‐1249‐5p/MCP‐1 axis is involved in macrophage‐associated inflammation in fatty liver injury in mice

Sphingosine 1-phosphate signaling in perivascular cells enhances inflammation and fibrosis in the kidney

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