Sphingosine 1-phosphate maintains naïve T cell by regulating apoptotic signaling
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE221482 | GEO | 2024/02/21
REPOSITORIES: GEO
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Project description:Sphingosine 1-phosphate (S1P) is a lysosphingolipid with anti-atherogenic properties, but mechanisms underlying its effects remain unclear. We here analyzed the consequences of overexpressing the S1P receptor type 1 (S1pr1) on peritoneal macrophage gene expression. To amplify S1pr1 signaling in macrophages, double transgenic mice expressing mouse S1pr1 in mononuclear cells were constructed by crossing two lines. The S1pr1-KI line carries a transgenic cassette in the Rosa 26 locus harboring the mouse S1P1 cDNA and separated from the CAG promoter by a lox-Stop-lox insert. S1pr1-KI mice were then crossed to LysMCre mice expressing Cre recombinase under the control of the lysozyme M promoter, which drives macrophage expression. In the offspring the lox-Stop-lox insert is excised in Cre-expressing cells (macrophages), which induces cDNA expression driven by the CAG promoter. At 12 weeks of age, peritoneal leukocytes were isolated from S1pr1-LysMCre mice and control mice (S1pr1-KI) by peritoneal lavage and seeded in cell culture plates. After 2 h non-adherent cells were removed, total RNA was isolated from the remaining macrophages and subjected to microarray gene expression analysis.
2024-11-07 | E-MTAB-14469 | biostudies-arrayexpress
Project description:Background: Myeloid cells (MCs) reside in the aortic intima at regions predisposed to atherosclerosis. Systemic inflammation triggers reverse transendothelial migration (RTM) of intimal MCs into arterial blood, which orchestrates a protective immune response that clears intracellular pathogens from the arterial intima. Molecular pathways that regulate RTM remain poorly understood. Sphingosine-1-phosphate (S1P) is a lipid mediator that regulates immune cell trafficking by signaling via five G protein-coupled receptors (S1PRs). We investigated the role of S1P in the RTM of aortic intimal MCs. Methods: Intravenous injection of lipopolysaccharide (LPS) was used to model a systemic inflammatory stimulus that triggers RTM. CD11c+ intimal MCs in the lesser curvature of the ascending aortic arch were enumerated by en face confocal microscopy. Local gene expression was evaluated by transcriptomic analysis of microdissected intimal cells. Results: In wild-type C57BL/6 mice, LPS induced intimal cell expression of S1pr1, S1pr3, and sphingosine kinase 1 (Sphk1, a kinase responsible for S1P production). Pharmacological modulation of multiple S1PRs blocked LPS-induced RTM and modulation of S1PR1 and S1PR3 reduced RTM in an additive manner. Cre-mediated deletion of S1pr1 in MCs blocked LPS-induced RTM, confirming a role for myeloid-specific S1PR1 signaling. Global or hematopoietic deficiency of Sphk1 reduced plasma S1P levels, the abundance of CD11c+ MCs in the aortic intima and blunted LPS-induced RTM. In contrast, plasma S1P levels, the abundance of intimal MCs, and LPS-induced RTM were rescued in Sphk1-/- mice transplanted with Sphk1+/+ or mixed Sphk1 +/+ and -/- bone marrow. Stimulation with LPS increased endothelial permeability and intimal MC exposure to circulating factors such as S1P. Conclusions: Functional and expression studies support a novel role for S1P signaling in the regulation of LPS-induced RTM as well as the homeostatic maintenance of aortic intimal MCs. Our data provides insight into how circulating plasma mediators help orchestrate intimal MC dynamics.
2024-02-22 | GSE252674 | GEO
Project description:Sphingosine 1-phosphate (S1P), a lipid chemoattractant, guides immune cells from the low-S1P environment of tissues into the high-S1P environment of circulatory fluids. Most notably, S1P directs T cell exit from lymph nodes (LN), where T cells are initially activated to fight pathogens, into lymph, from which T cells flow into blood and ultimately reach inflamed tissues. T cells follow these gradients primarily using S1P receptor 1 (S1PR1). The drugs Gilenya and Siponimod, both FDA-approved for the autoimmune disease multiple sclerosis, target S1PR1. They blind self-reactive T cells to S1P gradients, block them from exiting LN, and thus prevent them from infiltrating the central nervous system. While recent work has revealed key aspects of how S1P gradients are established at steady-state, very little is known about S1P distribution in disease, and in turn how changing S1P gradients may affect the immune response. Here, we find that LN S1P increases during an immune response, which prolongs the time T cells spend in the LN before exiting into lymph. Inflammatory monocytes, which had not previously been implicated in shaping S1P gradients, are an important source of this S1P. Inflammatory monocytes must express the early activation marker CD69 to supply S1P to T cells; CD69 represses transcription of S1P receptor 5 (S1pr5), enabling monocytes to infiltrate the LN T zone and efficiently release S1P. Here we compared RNA sequencing of inflammatory monocytes WT or CD69-KO infiltrating the draining lymph node.$
2020-12-23 | GSE139006 | GEO
Project description:Sphingosine 1-phosphate (S1P), a pro-tumor survival bioactive lysophospholipid, generated by sphingosine kinase 1 (SphK1), regulates lymphocyte egress into circulation via transducing S1P receptor 1 (S1PR1) signalling, and also plays a role in the differentiation of regulatory T cells and T helper-17 cells. However, the mechanisms by which receptor-independent SphK1/S1P signallng regulates anti-tumor T cell activity remain unknown. Using melanoma antigen gp100 reactive T cells deficient in Sphk1, we found that Pmel-Sphk1-/- T cells maintained central memory phenotype, showed higher mitochondrial respiration, and exhibited resistance to TGF-β mediated suppression. Mechanistically, we discovered a direct correlation between SphK1 generated intracellular S1P and PPARγ (peroxisome proliferator-activated receptor gamma) activity, which in turn regulate lipolysis in T cells. Genetic, molecular or pharmacologic inhibition of SphK1 or PPARγ improved metabolic fitness and anti-tumor activity of T cells. Further, inhibition of SphK1 and PD1 together led to long-term control of melanoma. Overall, these data highlight the clinical potential of targeting SphK1/S1P for improved anti-cancer adoptive T cell immunotherapy.
2019-07-31 | GSE129489 | GEO
Project description:Increased endothelial permeability and failure to repair is the hallmark of several vascular diseases including acute lung injury (ALI). However, little is known about the intrinsic pathways that activate endothelial cell (EC) regenerative programs and thereby tissue repair. Studies have invoked a crucial role of sphingosine-1-phosphate (S1P) in resolving endothelial hyperpermeability through activation of the G-protein coupled receptor, sphingosine-1-phosphate receptor 1 (S1PR1). Here, we addressed mechanisms of generation of S1PR1+ EC, which may prevent endothelial injury. Studies were made using inducible EC-S1PR1-/- (iEC-S1PR1-/-) mice and S1PR1-GFP reporter mice to trace the generation of S1PR1+ EC. We observed in a mouse model of endotoxemia that S1P generation induced the programming of S1PR1lo to S1PR1+ EC, which comprised 80% of lung EC. The transition of these cells was required for reestablishing the endothelial barrier. We also observed that conditional deletion of S1PR1 in EC increased vascular permeability. RNA-seq analysis of S1PR1+ EC showed enrichment of genes regulating S1P synthesis and transport, sphingosine kinase 1 (SPHK1) and SPNS2, respectively. The activation of transcription factors EGR1 and STAT3 were essential for transcribing SPHK1 and SPNS2, respectively, to increase S1P production that served to amplify S1PR1+ EC transition. Transplantation of S1PR1+ EC into injured lung vasculature restored endothelial integrity. Our findings show that generation of a S1PR1+ EC population activates the endothelial regenerative program mediating vascular endothelial repair, thus raising the possibility of harnessing this pathway to restore vascular homeostasis in inflammatory injury.
2023-01-15 | GSE165000 | GEO
Project description:Lung transplantation remains the only viable therapy for patients with end-stage lung disease; however, full utilization of this treatment strategy is severely compromised by the lack of donor lung availability. For example, the vast majority of donor lungs available for transplantation are obtained from brain death (BD) individuals. Unfortunately, the autonomic storm which accompanies BD often results in neurogenic pulmonary edema (NPE), thereby either producing irreversible lung injury or leading to primary graft dysfunction following lung transplantation. We previously demonstrated that sphingosine 1-phosphate (S1P), a phospholipid angiogenic factor and major barrier-enhancing agent, as well as S1P analogues serve to reduce vascular permeability and ischemia/reperfusion (I/R) lung injury in rodents via ligation of the S1P1 receptor, S1PR1. As primary lung graft dysfunction is induced by lung vascular endothelial cell barrier dysfunction, we hypothesized that SEW-2871, a S1PR1 agonist, may attenuate NPE when administered to the donor shortly after BD. Significant lung injury was observed 4h after BD in a rat BD model with ~60% increases in BAL total protein, BAL cell counts, and lung tissue W/D weight ratios. In contrast, rats receiving SEW-2871 (0.1 mg/kg) 15 minutes after the induction of BD and assessed 4h later exhibited significant lung protection (~50% reduction, p=0.01) reflected by reduced BAL total protein, BAL cytokines concentrations, BAL albumin, BAL total cell count and lung tissue wet/dry (W/D) weights ratio. Microarray analysis at 4hrs revealed a global impact of both BD and SEW on lung gene expression with differential expression of a subclass of genes enriched in immune/inflammation response pathways across the 4 experimental groups. Overall, SEW served to attenuate the BD-mediated ie gene expression upregulation. Two potentially useful biomarkers, Tnf and Ccrl2, exhibited gene dysregulation by microarray analysis, which was validated by qPCR. We conclude that SEW-2871 significantly attenuates BD-induced lung injury and may serve as a potential candidate to improve human lung donor availability and transplantation outcomes. Animals were divided into four groups: sham, BD (A Fogarty catheter 4 Fr. was inserted and secured into the extradural space and inflated to induce BD), SEW (injection of SEW-2871), and BD/SEW. Three replicates each.
2010-07-30 | E-GEOD-22531 | biostudies-arrayexpress
Project description:Naïve CD4 cells (CD45.2+CD4+,CD62L high,CD44 low) isolated from lymph nodes of mixed bone marrow chimeras 5 days after induced S1pr1 deletion.
2017-05-26 | GSE97249 | GEO
Project description:Background: Increased proliferation of airway smooth muscle (ASM) cells leading to hyperplasia and increased ASM mass is one of the most characteristic features of airway remodelling in asthma. A bioactive lipid, sphingosine-1-phosphate (S1P), has been suggested to affect airway remodelling by stimulation of human ASM cell proliferation. Objective: To investigate the effect of S1P on signalling and regulation of gene expression in ASM cells from healthy and asthmatic individuals. Methods: ASM cells grown from bronchial biopsies of healthy and asthmatic individuals were exposed to S1P. Gene expression was analysed using microarray, real-time PCR and western blotting. Receptor signalling and function was determined by mRNA knockdown and intracellular calcium mobilisation experiments. Results: S1P potently regulated the expression of more than 80 genes in human ASM cells, including several genes known to be involved in the regulation of cell proliferation and airway remodelling (HBEGF, TGFB3, TXNIP, PLAUR, SERPINE1, RGS4). S1P acting through S1P2 and S1P3 receptors activated intracellular calcium mobilisation and extracellular signal-regulated and Rho-associated kinases to regulate gene expression. S1P-induced responses were not inhibited by corticosteroids and did not differ significantly between ASM cells from healthy and asthmatic individuals. Conclusion: S1P induces a steroid-resistant, pro-remodelling pathway in ASM cells. Targeting S1P or its receptors could be a novel treatment strategy for inhibiting airway remodelling in asthma. Airway smooth muscle cells from 3 healthy donors were cultured and stimulated for 4 h with sphingosine-1-phosphate (100 nM) or medium control. Total RNA was extracted and analysed using Affymetrix Human Exon 1.0 ST arrays.
2015-06-18 | E-GEOD-58657 | biostudies-arrayexpress
Project description:Lymphocytes can circulate as well as take residence within tissues. The mechanisms by which circulating populations are recruited to infected tissue sites have been characterized, but the extent and molecular basis of tissue-resident cell recirculation is enigmatic. Here, we show that helminth infection- or IL-25-induced redistribution of intestinal tissue-localized group 2 innate lymphoid cells (ILC2s) requires access to the lymphatic vessel network even though secondary lymphoid structures, which are essential signal hubs for adaptive lymphocyte differentiation and dispatch, are dispensable for tissue ILC2 mobilization. IL-25 signals induce a dramatic change in epigenetic landscape of intestinal ILC2s, enabling the expression of sphingosine-1-phosphate (S1P) receptors. S1PR5 is critical for ILC2 exit from intestinal tissue to lymph, whereas S1PR1 plays a dominant role in ILC2 egress from mesenteric lymph nodes to blood circulation and then to lung, where redistributed ILC2s contribute to tissue repair. The requirement of two S1PRs is largely due to the dynamic expression of the tissue-retention marker CD69, which mediates S1PR1 internalization. This stage-specific requirement of different S1P receptors for ILC2 redistribution during infection illustrates that innate and adaptive lymphocytes share a circulatory network frame but employ specialized navigation cues for their distinct migratory requirements.
2024-06-05 | GSE268826 | GEO
Project description:Lymphocytes can circulate as well as take residence within tissues. The mechanisms by which circulating populations are recruited to infected tissue sites have been characterized, but the extent and molecular basis of tissue-resident cell recirculation is enigmatic. Here, we show that helminth infection- or IL-25-induced redistribution of intestinal tissue-localized group 2 innate lymphoid cells (ILC2s) requires access to the lymphatic vessel network even though secondary lymphoid structures, which are essential signal hubs for adaptive lymphocyte differentiation and dispatch, are dispensable for tissue ILC2 mobilization. IL-25 signals induce a dramatic change in epigenetic landscape of intestinal ILC2s, enabling the expression of sphingosine-1-phosphate (S1P) receptors. S1PR5 is critical for ILC2 exit from intestinal tissue to lymph, whereas S1PR1 plays a dominant role in ILC2 egress from mesenteric lymph nodes to blood circulation and then to lung, where redistributed ILC2s contribute to tissue repair. The requirement of two S1PRs is largely due to the dynamic expression of the tissue-retention marker CD69, which mediates S1PR1 internalization. This stage-specific requirement of different S1P receptors for ILC2 redistribution during infection illustrates that innate and adaptive lymphocytes share a circulatory network frame but employ specialized navigation cues for their distinct migratory requirements.
2024-06-27 | GSE270373 | GEO