Ceramide-1-Phosphate in Phagocytosis and Calcium Homeostasis

Abstract

Sphingolipids are well established sources of important signaling molecules. For example, ceramide (Cer) has been described as a potent inhibitor of cell growth and inducer of apoptosis. In contrast, ceramide 1-phosphate (C1P) has been reported to have mitogenic properties and to inhibit apoptosis. Our understanding of the distinct biological roles of C1P in the regulation of DNA synthesis, inflammation, membrane fusion, and intracellular Ca 2+ increase has rapidly expanded. C1P is a bioactive sphingolipid formed by the phosphorylation of ceramide catalyzed by ceramide kinase (CERK). This chapter specifically focuses on the role of C1P in phagocytosis and Ca 2+ homeostasis. Studies of the metabolism of C1P during phagocytosis, may lead to a better understanding of its role in signaling. Potentially, the inhibition of CERK and C1P formation may be a therapeutic target for inflammation. KeywordsCeramide-1-phosphate; ceramide kinase; phagocytosis; calcium; transient potential channel; fusion Ceramide-1-phosphate in PhagocytosisThe clearance of pathogens by the phagocytosis of opsonized, infectious agents is a vital biological process that is part of the innate immune system [1]. Phagocytosis is usually triggered by the interaction of target-bound opsonins with specific receptors on the surface of phagocytes. These receptors include the Fc receptors (FcRs), which bind to the Fc portion of immunoglobins [2], and the complement receptors [3], which bind to the complement deposited on targets. FcRs recognize the Fc portion of immunoglobins, and are expressed differentially on many cell types of the immune system [1]. Receptors for IgG (FcγR), IgE (FcεR) and IgA (FγA) have been characterized [1]. There are three classes of FcγRs: FcγRI, FcγRII, and FcγRIII. Each class consists of several receptor isoforms that are the product of different genes and splicing variants [2]. The interaction of FcRs with their immunoglobulin ligands triggers a series of leukocyte responses that include phagocytosis, the respiratory burst, antibody-dependent cell mediated cytotoxicity, the release of proinflammatory mediators, and the production of cytokines [1,4]. The activation of these receptors leads also to a reorganization of the plasma membrane that profoundly affects the 3 To whom correspondence should be addressed: Vania-Hinkovska-Galcheva, 109 Zina Pitcher Place, 4460 BSRB, Ann Arbor, Michigan 48109-2200; Tel:734-647-2903, Fax: 734-615-2331 function of phagocytes. The plasma membrane forms pseudopods that extend around an extracellular particle followed by fusion to form a membrane-bounded intracellular vesicle, termed the phagosome. As the process of phagocytosis proceeds, cytoplasmic granules fuse with the phagosome membrane to deliver hydrolytic and anti-bacterial enzymes to the phagosome [5]. Phagolysosome formation requires an increase in intracellular Ca 2+ and in addition to the recruitment of a complex containing docking and fusion proteins [6,7]. In contrast to apoptotic cells, Fc receptor-mediated phagocytosis of m...

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

“…This role was confirmed by various other groups as well, attributing the importance to C1P in the regulation of inflammatory response [69][70][71]. Besides this, C1P is also thought to have roles in the regulation of intracellular Ca 2+ levels [72][73][74].…”

Sphingolipids and Plant Defense/Disease: The “Death” Connection and Beyond

“…Switching this balance toward accumulation of ceramide may trigger PCD. This is reminiscent of the findings in animals that Cer-1-P and Ceramide are two antagonistic molecules in regulation of cell fate (Gomez-Munoz, 2004, 2006; Hinkovska-Galcheva and Shayman, 2010). One possible mechanism explaining Cer-1-P’s suppression of ceramide-induced PCD in animals is that Cer-1-P inhibits SPT activity, thereby inhibiting accumulation of ceramide from de novo synthesis (Granado et al, 2009).…”

The effect of the bioactive sphingolipids S1P and C1P on multipotent stromal cells – new opportunities in regenerative medicine

“…While BMSC cultures propagated under the influence of S1P demonstrated regular growth pattern, the ASCs exhibited the tendency to aggregate. Spontaneously formed cellular aggregates are characteristic of adipose-derived mesenchymal stem cells, especially in osteogenesis-promoting environment [56]. Although the addition of C1P into MSC cultures did not influence their morphology, a pro-proliferative effect of this agent was evident both in BMSC and ASC cultures.…”