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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE53670 | GEO | 2014/12/25

SECONDARY ACCESSION(S): PRJNA232617

REPOSITORIES: GEO

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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

Acid ceramidase regulates innate immune memory

Project description: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.

2023-11-27 | GSE188641 | GEO

Exosomes released from embryonic hippocampal cells under ceramide treatment carry a specific miRNA signature for sphingolipid pathway and cell differentiation

Project description:Purpose: Identification of the miRNA signature carried by the exosomes released from embryonic hippocampal cells under ceramide treatment Outcome: We investigated the role of ceramide in amplifying the differentiation signal of HN9.10 cells. Treatment of HN9.10 cells with ceramide caused the release of exosomes carrying neutral sphingomyelinase and neutral ceramidase. The analysis of exosomal miRNAs showed that 38 miRNAs were differentially expressed in a statistically significant manner, with some overexpressed miRNAs regulating genes encoding for proteins involved in biological, homeostatic, biosynthetic and small molecule metabolic processes, embryo development and cell differentiation, all phenomena that could be relevant for HN9.10 cell differentiation.

2023-07-12 | GSE228052 | 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

Detection of bacteria neutral ceramidase in diabetic foot ulcers with optimized substrate and chemoenzymatic probes

Project description:LC-MS proteomics for identification of neutral ceramidase for chemical probe pull-down

2023-08-30 | PXD040759 | JPOST Repository

Ichthyosis associated with sphingosine 1-phosphate lyase insufficiency syndrome is due to aberrant calcium and sphingolipid regulation

Project description:Sphingosine 1-phosphate lyase (SGPL1) insufficiency (SPLIS) is a syndrome which presents with adrenal insufficiency, steroid resistant nephrotic syndrome, hypothyroidism, neurological disease, and ichthyosis. Where a skin phenotype is reported, 94% presented with abnormalities such as ichthyosis, acanthosis, and hyperpigmentation. To elucidate the disease mechanism and the role SGPL1 plays in the skin barrier we established CRISPR-Cas9 SGPL1 knock-out and a lentiviral induced SGPL1 overexpression in nTERT immortalised keratinocytes and thereafter organotypic skin equivalents. Loss of SGPL1 caused an accumulation of S1P, sphingosine and ceramide while its overexpression caused a reduction of these species. RNAseq analysis showed perturbations in sphingolipid pathway genes, particularly in SGPL1_KO and GSEA revealed polar opposite differential gene expression between SGPL1_KO and _OE in keratinocyte differentiation and Ca2+ signalling genesets. SGPL1_KO upregulated differentiation markers while SGPL1_OE upregulated basal and proliferative markers. The advanced differentiation of SGPL1_KO was confirmed by 3D organotypic models that also presented with a thickened and retained stratum corneum, sphingolipid accumulation in the spinous layer and a breakdown of E-cadherin junctions. We hypothesise that SPLIS associated ichthyosis is a multi-faceted disease caused by sphingolipid imbalance and excessive S1P signalling.

2023-03-06 | GSE207499 | GEO

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

Comprehensive analysis of lipid metabolism-related enzymes including ceramide in skin of psoriasis patients

Project description:Ceramide is an important lipid in skin barrier function. Psoriasis is a chronic inflammatory skin disease, and the skin barrier function has disturbed. Furthermore, the balance of each ceramide species in stratum corneum is disrupted in psoriatic skin. However, it involved remains unclear what detailed mechanism ceramide species changed in psoriatic skin lesion. We comprehensively investigated lipid metabolism including ceramide in skin of psoriasis patients by DNA microarray analysis. The expression level of PNPLA1 gene involved in acylceramide synthesis which is epidermis-specific ceramide species essential for skin barrier function was decreased in psoriatic skin. In contrast, the expression level of lipid metabolism-related enzymes gene including ceramide were increased in psoriatic skin. Consequently, the acylceramide synthesis was decreased in skin of psoriasis patients, suggesting that increased biosynthesis of other sphingolipids to supplement the function of acylceramide may cause the pathology of psoriasis.

2024-03-16 | GSE168640 | GEO

Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice

Project description:Alcohol’s impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid-ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp. Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and lipid droplet compartments. We additionally demonstrate that hepatic ceramide reduction prevents alcohol’s inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri-lipid droplet ASAH expression in human ALD. Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD.

2020-07-08 | GSE139015 | GEO

ABCA12-mediated ceramide efflux governs breast cancer stem cell function

Project description:Cancer stem cells (CSCs) drive tumor growth, metastasis, relapse, and chemoresistance. However, it’s unclear how lipid metabolism, especially sphingolipids metabolism, regulates CSCs and chemoresistance. In this study, we developed spontaneous tumor models expressing a Sox9-GFP transgenic reporter and demonstrated that cancer cells expressing high levels of SOX9 functioned as CSCs in both primary tumors and metastases. Transcriptomics analyses uncovered that SOX9high CSCs upregulate ABCA12 lipid transporter. Functionally, downregulation of ABCA12 impaired cancer stemness and chemoresistance of SOX9high cells. Through lipidomic analysis, we demonstrated that ABCA12 regulates SOX9 expression and cancer stemness by controlling ceramide abundance. Blocking ceramide hydrolysis using acid ceramidase inhibitor D-NMAPPD sensitized tumors to chemotherapy and prevented enrichment of SOX9high CSCs. These data suggest a potential strategy for targeting CSCs and overcoming chemoresistance. We further demonstrated that ceramide inhibits the YAP/TAZ signaling that is required for SOX9 expression in breast CSCs.

2023-11-01 | GSE220178 | GEO

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