Functional roles of sphingolipids in immunity and their implication in disease

Immunology: Membrane lipids in immunity and diseaseAdvances in laboratory techniques and genetic databases are revealing the vital roles played by a large and complex family of lipids in immunity and disease. Sphingolipids, found in cell membranes, respond to environnmental cues to control cell signaling and metabolism. Initially named after the Sphinx because of their enigmatic nature, their complexity made detection difficult. Yoe-Sik Bae and co-workers at Sungkyunkwan University in Seoul, South Korea, have reviewed the discoveries made through methods such as mass spectrometry and integrated dataset analyses ('multi-omics'). For example, sphingolipid levels in the blood are affected by gut bacteria, cellular levels can determine whether cells live or die, and changes in sphingolipid populations have been linked to several diseases. Furthermore, analyzing the sphingolipid content in blood could aid diagnosis, because damaged organs express unique patterns of sphingolipid products. Sphingolipids, which are components of cellular membranes and organ tissues, can be synthesized or degraded to modulate cellular responses according to environmental cues, and the balance among the different sphingolipids is important for directing immune responses, regardless of whether they originate, as intra- or extracellular immune events. Recent progress in multiomics-based analyses and methodological approaches has revealed that human health and diseases are closely related to the homeostasis of sphingolipid metabolism, and disease-specific alterations in sphingolipids and related enzymes can be prognostic markers of human disease progression. Accumulating human clinical data from genome-wide association studies and preclinical data from disease models provide support for the notion that sphingolipids are the missing pieces that supplement our understanding of immune responses and diseases in which the functions of the involved proteins and nucleotides have been established. In this review, we analyze sphingolipid-related enzymes and reported human diseases to understand the important roles of sphingolipid metabolism. We discuss the defects and alterations in sphingolipid metabolism in human disease, along with functional roles in immune cells. We also introduce several methodological approaches and provide summaries of research on sphingolipid modulators in this review that should be helpful in studying the roles of sphingolipids in preclinical studies for the investigation of experimental and molecular medicines.