Sphingolipid metabolites in inflammatory disease

Abstract

Sphingolipids are ubiquitous building blocks of eukaryotic cell membranes. Progress in our understanding of sphingolipid metabolism, state-of-the-art sphingolipidomic approaches and animal models have generated a large body of evidence demonstrating that sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate, are signalling molecules that regulate a diverse range of cellular processes that are important in immunity, inflammation and inflammatory disorders. Recent insights into the molecular mechanisms of action of sphingolipid metabolites and new perspectives on their roles in regulating chronic inflammation have been reported. The knowledge gained in this emerging field will aid in the development of new therapeutic options for inflammatory disorders.

Figure 1. Sphingolipid metabolism and interconnected bioactive sphingolipid metabolites

a, Structure of ceramide, with a sphingosine backbone. b, De novo 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.

Figure 2. Subcellular compartmentalization of sphingolipid metabolism

De novo 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 trans-Golgi for biosynthesis of complex glycosphingolipids (GSLs). SM and GSLs are delivered to the plasma membrane by vesicular transport and C1P by a C1P-specific transfer protein (CPTP). For signalling at the plasma membrane, sphingomyelinase (SMase), ceramidase (CDase), and sphingosine kinases (SphK) produce the bioactive metabolites Cer, sphingosine (Sph) and sphingosine-1-phosphate (S1P), respectively. S1P is then transported across the membrane. Membrane sphingolipids are internalized by the endocytic pathway and in the lysosome they are degraded by acidic forms of SMase, glycosidase (GCase) and CDase. The Sph formed can be metabolized to glycerolipids after phosphorylation by SphKs (probably SphK1) and cleavage by S1P lyase (SPL) or reutilized for sphingolipid synthesis in the salvage pathway. In the nucleus, SphK2-produced S1P inhibits histone deacetylases.

Figure 3. S1P and S1PR1 control lymphocyte trafficking and vascular integrity

a, The sphingosine-1-phosphate (S1P) level in lymphoid tissues, such as the thymus, is low compared with the blood, forming an S1P gradient (shaded red) that attracts lymphocytes and promotes S1PR1-dependent egress into the blood. In the blood, S1P is bound to albumin (Alb) and apolipoprotein M (M) in high-density lipoprotein (HDL), and signalling by S1PR1 maintains endothelium barrier function by promoting cell–cell interactions (right). Conversely, ceramide (Cer) can promote barrier leakage. b, When T cells are ready to exit the thymus and enter the blood, S1PR1 is re-expressed so that T cells can respond to the chemotactic effect of high S1P levels in circulation. When T cells re-enter the blood, S1P downregulates S1PR1. Signals that control lymphocyte entry through high endothelial venules and retention in lymph nodes are not shown. Lymph node egress into lymphatic vessels also requires S1PR1. Increased lymphoid tissue S1P, by SPL inhibition, or in the presence of S1PR1 modulators such as FTY720, blocks egress of lymphocytes by disruption of the S1P gradient or desensitization of S1PR1 on T cells, respectively.

Figure 4. Ceramide at the nexus of obesity and inflammation

Ceramide is generated in response to obesity signals (such as saturated fatty acids, satFA), lipopolysaccharide (LPS) or pro-inflammatory cytokines (such as TNF) by enhancement of de novo biosynthesis or sphingolipid recycling. Ceramide can then signal to a variety of pathways that promote inflammation and the deleterious effects of obesity. Ceramide can bind to and inhibit SET/I2PP2A (not shown), leading to the activation of PP2A, which dephosphorylates and inhibits Akt, blocking many of the actions of insulin signalling and leading to insulin resistance, and decreased cell survival; activate PKCζ, also leading to the inhibition of Akt; induce autophagy, which can influence innate immune responses; activate the Nlrp3 inflammasome to promote the processing and secretion of the pro-inflammatory cytokines IL-1β and IL-18; and induce apoptosis. Binding of adiponectin to its receptors stimulates ceramidase (CDase), degrading ceramide to sphingosine, which is then phosphorylated to sphingosine-1-phosphate (S1P). Insulin stimulates Akt. It should be noted that this diagram is not meant to imply that all of these events occur in the same cell. CerS, ceramide synthase.