Lipidomic Profiling in Synovial Tissue

Abstract

The analysis of synovial tissue offers the potential for the comprehensive characterization of cell types involved in arthritis pathogenesis. The studies performed to date in synovial tissue have made it possible to define synovial pathotypes, which relate to disease severity and response to treatment. Lipidomics is the branch of metabolomics that allows the quantification and identification of lipids in different biological samples. Studies in animal models of arthritis and in serum/plasma from patients with arthritis suggest the involvement of different types of lipids (glycerophospholipids, glycerolipids, sphingolipids, oxylipins, fatty acids) in the pathogenesis of arthritis. We reviewed studies that quantified lipids in different types of tissues and their relationship with inflammation. We propose that combining lipidomics with currently used "omics" techniques can improve the information obtained from the analysis of synovial tissue, for a better understanding of pathogenesis and the development of new therapeutic strategies.

Keywords: arthritis; inflammation; lipidomics; synovial biopsies; synovitis.

Figure 1

Oxylipin synthesis. Pro-inflammatory oxylipins are marked in red, while anti-inflammatory ones are marked in blue. LOX, lipoxygenase; CYP, cytochrome; NE, non-enzymatic; PGDS, prostaglandin D synthase; PGFS, prostaglandin F synthase; PGES, prostaglandin E synthase; PGIS, prostaglandin I synthase; HEDH, Hydroxyeicosanoid dehydrogenase; LTAH, Leukotriene A4 hydrolase; PGDH, hydroxy prostaglandin dehydrogenase; TXAS, thromboxane A synthase; PGR, 15-ketoprostaglandinΔ13 reductase; sHE, soluble epoxide hydrolase.

Figure 2

Synthesis of phospholipids. Pro-inflammatory lipids are marked in red, while anti-inflammatory ones are marked in blue. ChoK, Choline Kinase; CDP-DGS, Cytidine diphosphate diacylglycerol Synthase; CPT, Carnitine Palmitoyltransferase; GPAT, glycerol-3-phosphate acyltransferase; ChoT, CholineTRansferasa; EK, Ethanolamine kinase; ET, Ethanolamine transferase; EPT, Ethanolalmine phosphotransferase; LPA acetyltransferase, lyso-phosphatidic acid acyltransferase; PA, Phosphatidic acid; PAP-1, Phosphatidate phosphatase-1; PC, Phosphatidylcholine; P-Choline, Phosphocholine PE, Phosphatidylethanolamine; P-Ethanolamine, Phosphoethanolamine; PLA1, Phospholipase A1; PLA2, Phospholipase A2; PEMT, PE methyltransferase; PS, Phosphatidylserine; PPS2, PS synthase 2; PSD, PS-decarboxylase.

Figure 3

Synthesis of sphingolipids. Pro-inflammatory lipids are marked in red, while anti-inflammatory ones are marked in blue.C1P, Ceramide 1-phosphate; CDase, Ceramidase; CerK, Ceramide Kinase; CerS, Ceramide Synthases 1–6; GCS, Glucosylceramide Synthase; SMS, Sphingomyelin synthase; SPT, Serine Palmitoyltransferase; S1P, Sphingosine 1-phosphate; SphK, Sphingosine kinase; *Different types of ceramides can act as either proinflammatory or anti-inflammatory.

Figure 4

Fatty acid synthesis. (A) De novo synthesis of endogenous fatty acids; ACYL, ATP citrate lyase; ACC1, Acetyl-coenzyme A carboxylase 1; FASN, fatty acid synthase; SCD1, stearoyl-CoA desaturase 1; ELOVL, elongase 6; (B) Synthesis of PUFA from essential fatty acids. ELOVL 2,4,5, elongases 2,4,5.

Figure 5

Summary of the role of bioactive lipids in synovial pathology. The findings included in the red circles include lipids with potential pro-inflammatory role, while the ones included in the blue circles include anti-inflammatory and pro-resolving metabolites. The black font describes results from studies in inflammatory arthritis, while the purple font describes results from studies in non-rheumatic diseases but with potential role in inflammatory arthritis. PUFA, polyunsaturated fatty acids; AA, arachidonic acid; LA, linoleic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; COX, cyclooxygenase; PGES, prostaglandin E synthase; LOX, lipoxygenase; PG, prostaglandin E; HETE, hydroxyeicosatetraenoic acid; LT, leukotriene; TX, thromboxane; HETrE, hydroxyeicosatrienoic acid; SPM, specialized proresolving mediators; Rv, resolvin; RA, rheumatoid arthritis; FLS, fibroblast-like synoviocytes; PE, phosphatidylethanolamine; TNF, tumor necrosis factor; S1P, sphingosine 1 phosphate; Cer, ceramides.