Sphingolipids in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the CNS. Oligodendrocytes, the myelin-forming cells of the central nervous system (CNS), are target cells in MS. Although the etiology of MS is poorly known, new insights suggest oligodendrocyte apoptosis as one of the critical events followed by glial activation and infiltration of lymphocytes and macrophages. A major breakthrough in delineation of the mechanism of cell death, perivascular cuffing, and glial activation came from elucidation of the sphingolipid signal transduction pathway. The sphingolipid signal transduction pathway induces apoptosis, differentiation, proliferation, and growth arrest depending upon cell and receptor types, and downstream targets. Sphingomyelin, a major component of myelin membrane formed by mature oligodendrocytes, is abundant in the CNS and ceramide, its primary catabolic product released by activation of either neutral or acidic sphingomyelinase, serves as a potential lipid second messenger or mediator molecule modulating diverse cellular signaling pathways. Similarly, under certain conditions, sphingosine produced from ceramide by ceramidase is phosphorylated by sphingosine kinases to sphingosine-1 phosphate, another potent second messenger molecule. Both ceramide and sphingosine-1 phosphate regulate life and death of many cell types including brain cells and participate in pathogenic processes of MS. In this review, we have made an honest attempt to compile recent findings made by others and us relating to the role of sphingolipids in the disease process of MS.

Fig. 1. Model showing the possible involvement of NSMase-ceramide pathway in cell death signaling in oligodendrocytes in MS

Oxidative stress-inducing agents directly activate the NSMase-ceramide pathway. On the other hand, NGF requires p75NTR while TNFα and Ca²⁺ use the phospholipase (PLA2) – arachidonic acid (AA) pathway to activate NSMase in oligodendrocytes.

Fig. 2. Schematic diagram showing the proposed role of S1P in MS

Activated T cells (Th1) expressing S1P receptor interacts with S1P found in blood during inflammation and enters the CNS where they produce proinflammatory cytotoxic products that promote oligodendrocytes death and demyelination. While CD8+ T cell directly kill oligodendrocytes through Fas and FasL interaction via ceramide pathway. Similarly B cells expressing S1PR enters the CNS and become plasma cells killing oligodendrocytes through ADCC pathway (antibody-dependant cell-mediated cytotoxicity). Astrocytes expressing S1PR undergoes gliosis via NSMase-ceramide pathway and utilizes the same pathway to release more proinflammatory cytotoxic products.