Molecular Mechanisms Underlying the Immunological Activities of Glycosphingolipid-Enriched Lipid Rafts in Phagocytes

Abstract

Phagocytes, such as neutrophils, macrophages, and dendritic cells, play crucial roles in the innate immune system. Innate immune responses are initiated by the binding of pathogens expressing highly conserved pathogen-associated molecular patterns (PAMPs) to a diverse array of pattern-recognition receptors expressed by phagocytes. On phagocytes, glycosphingolipids (GSLs) cluster together with cholesterol, glycophosphatidylinositol-anchored proteins, and various signaling molecules to form GSL-enriched lipid rafts. These GSL-enriched lipid rafts bind to several types of pathogens and their PAMPs, suggesting that these lipid rafts are essential for host–pathogen interactions in innate immunity. The neutral GSL lactosylceramide (LacCer, CDw17) binds to various microorganisms, including Candida and Mycobacteria. LacCer is expressed on plasma and granular membranes of mature human neutrophils and forms lipid rafts together with members of the Src family tyrosine kinases. These LacCer-enriched lipid rafts can mediate migration, phagocytosis of nonopsonized microorganisms, and superoxide generation. On plasma membranes, LacCer-enriched lipid rafts serve as signal transduction platform for CD11b/CD18 integrin (Mac-1, CR3, or αMβ2-integrin), indicating the importance of LacCer in a wide range of human innate immune responses. Especially, the interactions between LacCer-enriched lipid rafts and mycobacterial lipoarabinomannan (LAM) are significant for neutrophil phagocytosis of nonopsonized mycobacteria in human. We describe here the functional role of LacCer-enriched lipid rafts in human phagocytes.