The critical roles of bioactive sphingolipids in inflammation

Abstract

The bioactivity of sphingosine (Sph), ceramides, sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) has been known for decades. However, the molecular mechanisms by which these sphingolipids exert their biological actions are not completely understood. Initial studies showed that Sph inhibited protein kinase C and phosphatidate phosphohydrolase activities paving the way for further discoveries on the key role these sphingolipids play in signal transduction processes. Soon after the implication of Sph in cell signaling events, it was shown that ceramides were also able to regulate relevant cell functions, including cell death and survival, differentiation, autophagy, and inflammation. Subsequent studies showed that both Sph and ceramides could be phosphorylated in cells and that S1P and C1P counteracted many of the actions elicited by ceramides. Both phosphorylated sphingolipids are essential for regulation of many physiological and pathological cell processes. The present review has been undertaken to highlight and clarify the molecular mechanisms and signaling pathways that are regulated by Sph, ceramides, S1P and C1P in cells with special attention been paid to understand the role of these bioactive sphingolipids in inflammatory responses and inflammation-associated diseases.

Keywords: apoptosis; cancer; cell growth; ceramide; ceramide 1-phosphate; ceramide kinase; inflammation; sphingolipids; sphingosine; sphingosine 1-phosphate; sphingosine kinase.

Figure 1

Metabolic pathways of bioactive sphingolipids. Ceramides are the central core of sphingolipid metabolism. They can be synthesized by three major pathways: (1) the de novo synthesis pathway, in which serine palmitoyl-CoA transferase (SPT) and ceramide synthase (CerS) are the major regulatory enzymes of the pathway; (2) the sphingomyelinase (SMase) pathway, in which ceramides are generated directly from degradation of sphingomyelin (SM) by different SMases. The reversed reaction is catalyzed by SM synthase (SMS); (3) the salvage pathway, where sphingosine that is derived from the metabolism of complex sphingolipids is recycled back to ceramide by the action of CerS activity. Once generated, ceramide can be phosphorylated by ceramide kinase (CerK) to yield C1P, or it can be degraded by ceramidases (CDases) to form Sph. Subsequently S1P is synthesized through phosphorylation of Sph by sphingosine kinases (SphK). The reversed reaction is catalyzed by S1P phosphatases (SPP), or LPPs. S1P lyase degrades S1P to 2-trans hexadecenal and ethanolamine phosphate. C1P, ceramide 1-phosphate; LPP, lipid phosphate phosphatase; S1P, sphingosine 1-phosphate; SM, sphingomyelin.

Figure 2

Biological actions of S1P in mammalian cells. S1P can be synthesized intracellularly by the action of sphingosine kinases (SphKs) leading to stimulation of tumor necrosis factor-α-receptor-associated factor 2 (TRAF-2), telomere reverse transcriptase, prohibitin-2 or histone deacetylase activities. Intracellular S1P can be transported to the extracellular milieu by the ATP-binding cassette (ABC) family of transporters, sphingolipid transporter-2 (SPNS2), or major facilitator superfamily domain containing 2B (MFSD2B) transporter. The extracellular S1P pool can be increased by the action of extracellular SphKs acting on lipoprotein-derived Sph and by secretion of S1P from erythrocytes and platelets. Extracellular S1P can then interact with a family of five different G protein–coupled receptors (S1PR1-5) to regulate a variety of cell functions including glycogen and lipid metabolism, cell proliferation and survival, steroid hormone (cortisol and aldosterone) secretion, cell migration, vasodilatation, or participation in inflammatory responses. S1P, sphingosine 1-phosphate.

Figure 3

Biological actions of ceramides in mammalian cells. Accumulation of intracellular ceramides leads to inhibition of cell growth and stimulation of apoptosis through a variety of mechanisms including blockade of PLD, or inhibition of antiapoptotic Bcl-2 and activation of proapoptotic Bax proteins, respectively. Concerning inflammation, ceramides upregulate the NLRP3 inflammasome/caspase 1 axis, and cause mitochondrial dysfunction leading to proinflammatory cytokine production, being also implicated in the development of inflammation-associated diseases, such as obesity, steatosis, or atherosclerosis. Ceramides are also involved in insulin resistance through a mechanism involving Akt/PKB (protein kinase B) inhibition. PLD, phospholipase D.

Figure 4

Biological actions of C1P in mammalian cells. C1P is synthesized intracellularly by the action of ceramide kinase (CerK) leading to regulation of cell proliferation, apoptosis, and inflammation. C1P is also found in the extracellular milieu, being able to interact with a specific membrane-binding site (possibly a GPCR) that is coupled to Gi proteins. Binding of C1P to its putative receptor leads to regulation of cell migration through upregulation of metalloproteinases 2 and 9 (MMP 2 and 9), also implying the release of macrophage chemoattractant protein 1 (MCP1). Also, extracellular C1P promotes glucose uptake through a mechanism involving stimulation of the GLUT-3 glucose transporter in macrophages. C1P, ceramide 1-phosphate; GPCR, G protein–coupled receptor.