Modulation of Inflammation by Lipids in the Brain: The Cross-Talk Among Lipid Metabolites and Induction of Lipo-Toxicity

Neural cell membranes consist of phospholipids, sphingolipids, cholesterol and proteins. Phospholipids and sphingolipids contribute to the lipid asymmetry, whereas cholesterol and sphingolipids form lipid microdomains or lipid rafts. Lipid rafts float within the membrane, and certain groups of proteins unite within these rafts. A large number of signaling molecules are concentrated within rafts. In response to cell stimulation or injury, phospholipids, sphingolipids, and cholesterol generate lipid metabolites, which promote or block inflammation in the body. Thus, phospholipids release arachidonic acid or docosahexaenoic acid from the sn-2 position of glycerol moiety by the action of phospholipase A2. Arachidonic acid is a precursor for eicosanoids, a group of metabolites, which includes prostaglandins, leukotrienes, thromboxane, and lipoxins. These metabolites are not only involved in the cell proliferation, differentiation, blood clotting, and blood vessel permeability, but also promote the induction of inflammation, immune responses, and gene expression. In contrast, metabolism of docosahexaenoic acid generates, specialized pro-resolving lipid metabolites called resolvins, protectins, and maresins. These metabolites regulate immune function by producing resolution of inflammation, a cell protective mechanism. Sphingolipid derived-metabolites, particularly ceramide, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate regulating a diverse range of cellular processes including inflammation. Among cholesterol-derived metabolites (24-hydroxy, 25-hydroxy, and 7-ketocholesterlcholesterol), unesterified 7-ketocholesterol disrupts fluidity and alters signaling pathways associated with inflammation, oxidative stress, and apoptosis leading to cellular damage and death. The cross-talk among phospholipid, sphingolipid, and cholesterol-derived lipid metabolites modulates the intensity of inflammation, a process that contributes to lipo-toxicity and cell death.