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Glycosphingolipids (GSLs), together with cholesterol, sphingomyelin (SM), and glycosylphosphatidylinositol (GPI)-anchored and membrane-associated signal transduction molecules, form GSL-enriched microdomains. These specialized microdomains interact in a cis manner with various immune receptors, affecting immune receptor-mediated signaling. This, in turn, results in the regulation of a broad range of immunological functions, including phagocytosis, cytokine production, antigen presentation and apoptosis. In addition, GSLs alone can regulate immunological functions by acting as ligands for immune receptors, and exogenous GSLs can alter the organization of microdomains and microdomain-associated signaling. Many pathogens, including viruses, bacteria and fungi, enter host cells by binding to GSL-enriched microdomains. Intracellular pathogens survive inside phagocytes by manipulating intracellular microdomain-driven signaling and/or sphingolipid metabolism pathways. This review describes the mechanisms by which GSL-enriched microdomains regulate immune signaling.

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Membrane microdomains, also called lipid rafts, are areas on membrane enriched in glycolipids, sphingolipids, and cholesterol. Although membrane microdomains are thought to play key roles in many cellular functions, their structures, properties, and biological functions remain obscure. Cellular membranes contain several types of glycoproteins, glycolipids, and other lipids, including cholesterol, glycerophospholipids, and sphingomyelin. Depending on their physicochemical properties, especially the characteristics of their glycolipids, various microdomains form on these cell membranes, providing structural or functional contextures thought to be essential for biological activities. For example, the plasma membranes of human neutrophils are enriched in lactosylceramide (LacCer) and phosphatidylglucoside (PtdGlc), each of which forms different membrane microdomains with different surrounding molecules and is involved in different functions of neutrophils. Specifically, LacCer forms Lyn-coupled lipid microdomains, which mediate neutrophil chemotaxis, phagocytosis, and superoxide generation, whereas PtdGlc-enriched microdomains mediate neutrophil differentiation and spontaneous apoptosis. However, the mechanisms by which these glycolipids form different nano/meso microdomains and mediate their specialized functions remain incompletely understood. This review describes current understanding of the roles of glycolipids and sphingolipids in their enriched contextures on cellular membranes, including their mechanisms of facilitation and regulation of intracellular signaling. This review also introduces new concepts about the roles of glycolipid and sphingolipiddependent contextures in immunological functions.

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