Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Acid ceramidase regulates innate immune memory

ABSTRACT: Innate immune memory, also called "trained immunity," is a metabolically and epigenetically regulated functional state of myeloid cells. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We found that exogenously administered sphingolipids and inhibition of enzymes involved in sphingolipid metabolism modulate trained immunity. In particular, we found that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We discovered that acid ceramidase regulates the expression of genes encoding histone-modifying enzymes, resulting in profound changes in the epigenetic landscape. We confirmed our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal a novel immunomodulatory effect of sphingolipids, provide new insight into the metabolic regulation of trained immunity, and identify acid ceramidase as a therapeutic target to modulate it.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188641 | GEO | 2023/11/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease

Project description:Macrophages have important protective functions during infection with herpes simplex virus type 1 (HSV-1). However, molecular mechanisms that restrict viral propagation and protect from severe disease are unclear. Here we found that macrophages take up HSV-1 via endocytosis and transport the virions into multivesicular bodies (MVBs). In MVBs, acid ceramidase (aCDase) converts ceramide into sphingosine and increases the formation of sphingosine-rich intraluminal vesicles (ILVs). Once HSV-1 particles pass MVBs, sphingosine-rich ILVs bind to HSV-1 particles, which restricts fusion with the limiting endosomal membrane and prevents cellular infection. Lack of aCDase in macrophage cultures or in Asah1–/– mice results in replication of HSV-1 and Asah1–/– mice died soon after systemic or intravaginal inoculation. The treatment of macrophages with sphingosine enhancing compounds blocks HSV-1 propagation, suggesting a therapeutic potential of this pathway. In conclusion, we demonstrate that aCDase loads ILVs with sphingosine, which prevents HSV-1 capsids from penetrating into the cytosol.

2020-01-14 | GSE142175 | GEO

Polyploid Giant Cancer Cells are dependent on cholesterol for progeny formation through amitotic division

Project description:Polyploid Giant Cancer Cells (PGCC) are increasingly being studied for their role in cancer recurrence and mortality. These cells are induced in bulk cancer cell populations when under stress such as hypoxia or treatment stress (i.e. chemotherapy or radiation). PGCC utilize temporary senescence achieved via a dedifferentiation pathway to survive transient stresses, providing a seed population for later regrowth. Our previous work demonstrated a dependence on the lysosomal enzyme acid ceramidase (ASAH1) in these cells, such that they are unable to perform division without ASAH1. The pro-drug LCL521 is lysosomally targeted, fully inhibits ASAH1 activity within 5 hours, and ablates the ability of PGCC to generate progeny while permitting mitotic cancer cells to proliferate normally. We used an RNASeq approach to compare the responses of parental PPC1 prostate cancer cells and their radiation-induced PGCC counterparts to 5 hours of LCL-521 treatment. RNASeq confirmed that no major changes were triggered in parental PPC1 cells while PGCC appeared to respond as if they had undergone cholesterol depletion.

2022-06-01 | GSE195919 | GEO

Presence of ceramidase activity in electronegative LDL

Project description:Electronegative LDL (LDL(-)) is a minor modified fraction of human plasma LDL with several atherogenic properties. Among them, LDL(-) has increased content of bioactive lipid mediators, such as lysophosphatidylcholine (LPC), non-esterified fatty acids (NEFA), ceramide (Cer), and sphingosine (Sph), which are related to the presence in LDL(-) of some phospholipolytic activities, including platelet-activating factor acetylhydrolase (PAF-AH), phospholipase C (PLC) and sphingomyelinase (SMase). However, the activity of these enzymes does not explain the increased content of Sph, which should derive from Cer degradation. In the present study we analyzed the putative presence of a ceramidase (CDase) activity that could explain the increased content of Sph. Thin layer chromatography (TLC) and lipidomic analysis showed that Cer, Sph and NEFA spon-taneously increased in LDL(-) incubated alone at 37ºC, in contrast with native LDL(+). An inhibitor of neutral CDase prevented the formation of Sph and, in contrast, increased the content of Cer in LDL(-). In addition, a fluorescently-labelled Cer (NBD-Cer) was efficiently degraded by LDL(-) to form Sph and NEFA. These observations point to the existence of a CDase activity associated to LDL(-). However, neither proteomic analysis nor western blot detected the presence of a known CDase enzyme. Further studies are warranted to define the origin of the CDase activity detected in LDL(-).

2023-01-09 | PXD036168 | Pride

Pseudomonas-derived Ceramidase Induces Production of Inflammatory Mediators from Human Keratinocytes via Sphingosine-1-Phosphate

2014-12-25 | GSE53670 | GEO

Aldosterone induces trained immunity: the role of fatty acid synthesis.

Project description:Supranormal levels of aldosterone are associated with increased cardiovascular risk in humans, and with accelerated atherosclerosis in animal models. Atherosclerosis is a low-grade inflammatory disorder, with monocyte-derived macrophages as major drivers of plaque formation. Monocytes can adopt a long-term pro-inflammatory phenotype after brief stimulation with microbial pathogens or endogenous atherogenic lipoproteins via a process termed trained immunity. Using a primary human in vitro model, we demonstrate that aldosterone induces trained immunity via the mineralocorticoid receptor. We identify fatty acid synthesis as a crucial pathway necessary for the induction of trained immunity in monocyte-derived macrophages and demonstrate that pharmacological inhibition of this pathway blunts aldosterone-induced trained immunity. At the level of gene regulation, aldosterone promotes enrichment of the transcriptionally-permissive H3K4me3 modification at promoters of genes central to the fatty acid synthesis pathway. These data provide mechanistic insight into the contribution of aldosterone to inflammation, atherosclerosis and cardiovascular disease.

2020-09-21 | GSE121696 | GEO

scRNAseq of monocytes from Trained immunity experiments

Project description:scRNAseq of monocytes from in vitro Trained immunity experiments stimulated by β-glucan (BG), uric acid (UA), muramyl dipeptide (MDP), oxidized low-density lipoprotein (oxLDL), or RPMI-Control, and respective samples restimulated with Lipopolysaccharide (LPS).

2021-09-30 | E-MTAB-9702 | biostudies-arrayexpress

Pseudomonas-derived Ceramidase Induces Production of Inflammatory Mediators from Human Keratinocytes via Sphingosine-1-Phosphate

Project description:A Pseudomonas aeruginosa-derived neutral ceramidase (PaCDase) isolated from a patient with atopic dermatitis was shown to effectively degrade ceramide in the presence of Staphylococcus aureus-derived lipids or neutral detergents. To understand the effect of ceramide metabolites on the functions of differentiating keratinocytes, we have conducted genes expressions analysis from PaCDase-, sphingosine-1-phosphate (S1P)-treated or untreated three-dimensionally cultured human primary keratinocytes, which form a stratum corneum, in the presence of Triton X-100 using high resolution DNA microarray. To evaluate the effects of PaCDase and S1P on keratinocyte functions, we applied an epicutaneous 24-h patch test on the EPI-Model in keratinocyte serum-free medium (keratinocyte-SFM) (Invitrogen; Carlsbad, CA, USA) by the method of Spiekstra et al. [25] with some modification. The Triton X-100 treated samples were labeled using Cy5, and the PaCDase or S1P samples were labeled with Cy3.

2014-12-25 | E-GEOD-53670 | biostudies-arrayexpress