Multiplicity of Glycosphingolipid-Enriched Microdomain-Driven Immune Signaling

Abstract

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.

Sulfatide inhibits fibroblast growth, activation and oxidative stress induced by ectopic insulin

“…A possible mechanism of how glycolipids affect the receptor is by influencing the receptor microenvironment. Glycolipids are not located at random but occur in organized microdomains or rafts in the plasma membrane 37,38 . Receptors for IGF‐1 and epidermal growth factor are located in such rafts 39,40 and their function is conceivably affected by the glycolipid composition of the raft.…”

A prognostic model based on regulatory T‐cell‐related genes in gastric cancer: Systematic construction and validation

“…This suggests that this pathway is involved in regulation of immune inflammation. In glycosphingolipid biosynthesis ganglio series pathway, the glycosphingolipid‐rich microdomain is associated with receptor‐mediated immune signalling, which is stimulated in macrophages and neutrophils (and dendritic cells) leading to pathogen clearance 38 . Gangliosides, as a form of sialoglycosphingolipid, have been shown to be therapeutic targets for neuroblastoma 39 .…”

Glycosphingolipid and Glycosylphosphatidylinositol Affect Each Other in and on the Cell

“…Thus, GM3 is a key component of the lipid rafts involved in signaling through GPI‐APs [40] . Moreover, the lipid rafts are also involved in T cell biology, for example, the functioning of cytokine/chemokine receptors, antigen presentation, phagocytosis, apoptosis, and pathogen – T cell interaction [67,68] . The human neutrophil urokinase plasminogen activator (uPA) is a GPI‐AP engaged in neutrophil activation through interactions with the uPA receptor (uPAR) [69] .…”

“…[40] Moreover, the lipid rafts are also involved in T cell biology, for example, the functioning of cytokine/ chemokine receptors, antigen presentation, phagocytosis, apoptosis, and pathogen -T cell interaction. [67,68] The human neutrophil urokinase plasminogen activator (uPA) is a GPI-AP engaged in neutrophil activation through interactions with the uPA receptor (uPAR). [69] Lipid raft-disrupting agents was able to promote uPAR-uPA crosslinkage to stimulate uPAR.…”

“…Many human pathogens enter the host cell through GSLenriched microdomains of the cell membrane or avoid immune surveillance through manipulating GSL-mediated signaling and the metabolic pathways of GSLs. [68] Therefore, the lipid rafts play a critical role in pathogenic immunology and signaling. LacCer is expressed at a high level and forms lipid rafts in the cell membrane of human neutrophils, to which many microorganisms bind.…”