W

W. with the condensation of palmitoyl coenzyme A (CoA) and serine by serine palmitoyltransferase (SPT), an enzyme that is negatively regulated by ORM1-like protein 3 (ORMDL3). This is followed by a series of reactions (catalysed by enzymes in red) leading to formation of ceramide and subsequent formation of sphingomyelin and glycosphingolipids. Ceramide can be metabolized to other bioactive sphingolipid species, phosphorylated by ceramide kinase (CERK) to ceramide-1-phosphate (C1P), or hydrolysed to sphingosine, which is usually then phosphorylated to sphingosine-1-phosphate (S1P) by sphingosine kinases (SphKs). S1P can be degraded by phosphatases to sphingosine or by the lyase (SPL) that cleaves it to phosphoethanolamine and hexadecenal, which are subsequently reincorporated into glycerolipid metabolic pathways. For simplicity, degradative enzymes (blue) for reutilization of sphingolipids in the salvage pathway are included but these reactions take place in different subcellular compartments (see Fig. 2). CDase, ceramidase; CerS, ceramide synthase; GCase, glucosylceramidase; GCS, glucosylceramide synthase; Pase, phosphatase; PtdEtn, phosphatidylethanolamine; SMase, sphingomyelinase; SMS, sphingomyelin synthase; SPPase, sphingosine phosphate phosphatase. The past decade has seen an explosive advancement in the field of sphingolipid signalling based on the convergence of several key aspects. First, most of the regulatory proteins and enzymes involved in sphingolipid metabolism and the receptors for S1P have been cloned. This allowed the generation of knockout mice, yielding insights into the physiological functions of sphingolipid metabolites. Second, the advent of advanced mass spectroscopic techniques has brought the omics revolution to sphingolipids, allowing for the simultaneous analysis and quantification of multiple species. Third, specific agonists and antagonists of S1P receptors and inhibitors of signalling enzymes were developed. The chief development among these was the discovery of FTY720 (fingolimod), a sphingosine analogue that alters immune cell trafficking and is already being used in the clinic for the treatment of multiple sclerosis4. These are exciting times for the field and research continues apace. Several sphingolipid signalling protein structures have been solved, allowing for rational drug design. This Review will focus on the function of three key bioactive sphingolipids: ceramide, C1P and S1P, and their roles in inflammation. Although this is a normal physiological response to harmful stimuli such as infection, unchecked inflammation can lead to numerous pathophysiological says, including oedema, asthma, inflammatory bowel disease and associated cancer, and autoimmune disorders such as multiple sclerosis and rheumatoid arthritis. Sphingolipid metabolites play crucial parts at multiple stages of these disorders, and new mechanistic perspectives on their actions will be discussed. We will also highlight how knowledge gained in this relatively new field will aid in the development of therapeutic options for inflammatory disorders. Sphingolipid metabolism Sphingolipids are essential lipids consisting of a sphingoid backbone that is ceramide (Cer) synthesis takes place in the endoplasmic reticulum (ER). Cer is delivered by ceramide transport protein (CERT) or vesicular transport to the Golgi for synthesis of ceramide-1-phosphate (C1P) (by ceramide kinase, CERK), sphingomyelin (SM), and glucosylceramide (GluCer). Four-phosphate adaptor protein 2 (FAPP2) then transports GluCer to the biosynthesis. Ceramide triggers several pathways that induce endothelial cell death, including activation of caspases, or PP1 AZD7687 or PP2A2,55, and increasing mitochondrial permeability by forming ceramide-enriched platforms capable of translocating proteins. Moreover, PAF-induced formation of ceramide microdomains drives endothelial nitric oxide synthase (eNOS) activation and contributes to barrier dysfunction56. Ceramides have also been linked to growth arrest, cytoskeleton rearrangements, oxidative stress and senescence of endothelial cells2. Thus, ceramides regulate important endothelial cell functions that are thought to be responsible for the pathogenesis associated with vascular dysfunctions, including emphysema, sepsis and acute respiratory distress syndrome. Using animal models of acute and chronic inflammation, it has been convincingly demonstrated that plasma S1P limits disruption of vascular endothelial monolayers and reduces oedema57.Sphingosine and its relatives continue to surprise and confound us today. include ceramide (sphingolipid biosynthesis starts with the condensation of palmitoyl coenzyme A (CoA) and serine by serine palmitoyltransferase (SPT), an enzyme that is negatively regulated by ORM1-like protein 3 (ORMDL3). This is followed by a series of reactions (catalysed by enzymes in red) leading to formation of ceramide and subsequent formation of sphingomyelin and glycosphingolipids. Ceramide can be metabolized to other bioactive sphingolipid species, phosphorylated by ceramide kinase (CERK) to ceramide-1-phosphate (C1P), or hydrolysed to sphingosine, which is then phosphorylated to sphingosine-1-phosphate (S1P) by sphingosine kinases (SphKs). S1P can be degraded by phosphatases to sphingosine or by the lyase (SPL) that cleaves it to phosphoethanolamine and hexadecenal, which are subsequently reincorporated into glycerolipid metabolic pathways. For simplicity, degradative enzymes (blue) for reutilization of sphingolipids in the salvage pathway are included but these reactions take place in different subcellular compartments (see Fig. 2). CDase, ceramidase; CerS, ceramide synthase; GCase, glucosylceramidase; GCS, glucosylceramide synthase; Pase, phosphatase; PtdEtn, phosphatidylethanolamine; SMase, sphingomyelinase; SMS, sphingomyelin synthase; SPPase, sphingosine phosphate phosphatase. The past decade has seen an explosive advancement in the field of sphingolipid signalling based on the convergence of several key aspects. First, most of the regulatory proteins and enzymes involved in sphingolipid metabolism and the receptors for S1P have been cloned. This allowed the generation of knockout mice, yielding insights into the physiological functions of sphingolipid metabolites. Second, the advent of advanced mass spectroscopic techniques has brought the omics revolution to sphingolipids, allowing for the simultaneous analysis and quantification of multiple species. Third, specific agonists and antagonists of S1P receptors and inhibitors of signalling enzymes were developed. The chief development among these was the discovery of FTY720 (fingolimod), a sphingosine analogue that alters immune cell trafficking and is already being used in the clinic for the treatment of multiple sclerosis4. These are exciting times for the field and research continues apace. Several sphingolipid signalling protein structures have been solved, allowing for rational drug design. This Review will focus on the function of three key bioactive sphingolipids: ceramide, C1P and S1P, and their roles in inflammation. Although this is a normal physiological response to harmful stimuli such as infection, unchecked inflammation can lead to numerous pathophysiological states, including oedema, asthma, inflammatory bowel disease and associated cancer, and autoimmune disorders such as multiple sclerosis and rheumatoid arthritis. Sphingolipid metabolites play crucial parts at multiple stages of these disorders, and new mechanistic perspectives on their actions will be discussed. We will also highlight how knowledge gained in this relatively new field will aid in the development of therapeutic options for inflammatory disorders. Sphingolipid metabolism Sphingolipids are essential lipids consisting of a sphingoid backbone that is ceramide (Cer) synthesis takes place in the endoplasmic reticulum (ER). Cer is delivered by ceramide transport protein (CERT) or vesicular transport to the Golgi for synthesis of ceramide-1-phosphate (C1P) (by ceramide kinase, CERK), sphingomyelin (SM), and glucosylceramide AZD7687 (GluCer). Four-phosphate adaptor protein 2 (FAPP2) then transports GluCer to the biosynthesis. Ceramide triggers several pathways that induce endothelial cell death, including activation of caspases, or PP1 or PP2A2,55, and increasing mitochondrial permeability by forming ceramide-enriched platforms capable of translocating proteins. Moreover, PAF-induced formation of ceramide microdomains drives endothelial nitric oxide synthase (eNOS) activation and contributes to barrier dysfunction56. Ceramides have also been linked to growth arrest, cytoskeleton rearrangements, oxidative stress and senescence of endothelial cells2. Thus, ceramides regulate important endothelial cell functions that are thought to be responsible for the pathogenesis associated with vascular dysfunctions, including emphysema, sepsis and acute respiratory distress syndrome. Using animal models of acute and chronic inflammation, it has been AZD7687 convincingly demonstrated that plasma S1P limits disruption of vascular endothelial monolayers and reduces oedema57 (Fig. 3a). S1P activates endothelial S1PR1, leading to enhanced Rac-dependent cytoskeleton rearrangements, contacts between cells and the matrix, adherens junction assembly and barrier integrity3,41. Lymphocytes circulate through lymph nodes for immune surveillance, entering at high endothelial venules AZD7687 (HEVs) specialized blood vessels. Until recently, it was not known how HEVs allow lymphocyte transmigration, which increases during immune responses, and maintain vascular integrity. A study demonstrated that podoplanin expressed on HEV fibroblastic reticular cells binds and activates platelet C-type lectin-like receptor-2 (CLEC2)58. Activation of CLEC2 on extravasated platelets leads to the.42). J. L. W. Thudichum presciently named the brain lipid sphingosine after the Sphinx, owing to its enigmatic chemical nature1. Sphingosine and its relatives continue to surprise and confound us today. These fatty amino alcohols are the backbone of a ubiquitous class of eukaryotic lipids, the sphingolipids, which include ceramide (sphingolipid biosynthesis starts with the condensation of palmitoyl coenzyme A (CoA) and serine by serine palmitoyltransferase (SPT), an enzyme that is negatively regulated by ORM1-like protein 3 (ORMDL3). This is followed by a series of reactions (catalysed by enzymes in red) leading to formation of ceramide and subsequent formation of sphingomyelin and glycosphingolipids. Ceramide can be metabolized to additional bioactive sphingolipid varieties, phosphorylated by ceramide kinase (CERK) to ceramide-1-phosphate (C1P), or hydrolysed to sphingosine, which is definitely then phosphorylated to sphingosine-1-phosphate (S1P) by sphingosine kinases (SphKs). S1P can be degraded by phosphatases to sphingosine or from the lyase (SPL) that cleaves it to phosphoethanolamine and hexadecenal, which are consequently reincorporated into glycerolipid metabolic pathways. For simplicity, degradative enzymes (blue) for reutilization of sphingolipids in the salvage pathway are included but these reactions take place in different subcellular compartments (observe Fig. 2). CDase, ceramidase; CerS, ceramide synthase; GCase, glucosylceramidase; GCS, glucosylceramide synthase; Pase, phosphatase; PtdEtn, phosphatidylethanolamine; SMase, sphingomyelinase; SMS, sphingomyelin synthase; SPPase, sphingosine phosphate phosphatase. The past decade has seen an explosive advancement in the field of sphingolipid signalling based on the convergence of several key aspects. First, most of the regulatory proteins and enzymes involved in sphingolipid metabolism and the receptors for S1P have been cloned. This allowed the generation of knockout mice, yielding insights into the physiological functions of sphingolipid metabolites. Second, the introduction of advanced mass spectroscopic techniques has brought the omics revolution to sphingolipids, allowing for the simultaneous analysis and quantification of multiple varieties. Third, specific agonists and antagonists of S1P receptors and inhibitors of signalling enzymes were developed. The chief development among these was the finding of FTY720 (fingolimod), a sphingosine analogue that alters immune cell trafficking and is already being used in the medical center for the treatment of multiple sclerosis4. These AZD7687 are fascinating occasions for the field and study continues apace. Several sphingolipid signalling protein structures have been solved, allowing for rational drug design. This Review will focus on the function of three key bioactive sphingolipids: ceramide, C1P and S1P, and their functions in swelling. Although this is a normal physiological response to harmful stimuli such as infection, unchecked swelling can lead to numerous pathophysiological claims, including oedema, asthma, inflammatory bowel disease and connected malignancy, and autoimmune disorders such as multiple sclerosis and rheumatoid arthritis. Sphingolipid metabolites play important parts at multiple phases of these disorders, and fresh mechanistic perspectives on their actions will become discussed. We will also spotlight how knowledge gained in this relatively fresh field will aid in the development of restorative options for inflammatory disorders. Sphingolipid rate of metabolism Sphingolipids are essential lipids consisting of a sphingoid backbone that is ceramide (Cer) synthesis takes place in the endoplasmic reticulum (ER). Cer is definitely delivered by ceramide transport protein (CERT) or vesicular transport to the Golgi for synthesis of ceramide-1-phosphate (C1P) (by ceramide kinase, CERK), sphingomyelin (SM), and glucosylceramide (GluCer). Four-phosphate adaptor protein 2 (FAPP2) then transports GluCer to the biosynthesis. Ceramide causes several pathways that induce endothelial cell death, including activation of caspases, or PP1 or PP2A2,55, and increasing mitochondrial permeability by forming ceramide-enriched platforms capable of translocating proteins. Moreover, PAF-induced formation of ceramide microdomains drives endothelial nitric oxide synthase (eNOS) activation and contributes to barrier dysfunction56. Ceramides have also been linked to growth arrest, cytoskeleton rearrangements, oxidative stress and senescence of endothelial cells2. Therefore, ceramides regulate important endothelial cell functions that are thought to be responsible for the pathogenesis associated with vascular dysfunctions, including emphysema, sepsis and acute respiratory distress syndrome. Using animal models of acute and chronic swelling, it has been convincingly shown that plasma S1P limits disruption of vascular endothelial monolayers and reduces oedema57 (Fig. 3a). S1P activates endothelial S1PR1, leading to enhanced Rac-dependent cytoskeleton rearrangements, contacts between cells and the matrix, adherens junction assembly and barrier integrity3,41. Lymphocytes circulate through lymph nodes for immune surveillance, entering at high endothelial venules (HEVs) specialized blood vessels. Until recently, it was not known how HEVs allow lymphocyte transmigration, which raises during immune reactions, and maintain vascular integrity. A study shown that podoplanin indicated on HEV fibroblastic reticular cells binds and activates platelet C-type lectin-like receptor-2 (CLEC2)58. Activation of CLEC2 on extravasated platelets prospects to the launch of S1P MMP26 in the perivenular space of HEVs. S1P, in turn, enhances vascular endothelial (VE)-cadherin manifestation for maintenance of.