Mayo L, Trauger SA, Blain M, Nadeau M, Patel B, Alvarez JI, Mascanfroni ID, Yeste A, Kivisäkk P, Kallas K, Ellezam B, Bakshi R, Prat A, Antel JP, Weiner HL, Quintana FJ. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med. 2014 Sep. doi: 10.1038/nm.3681. [Epub ahead of print]
Astrocytes have complex roles in health and disease, thus it is important to study the pathways that regulate their function. Here we report that lactosylceramide (LacCer) synthesized by β-1,4-galactosyltransferase 6 (B4GALT6) is upregulated in the central nervous system (CNS) of mice during chronic experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). LacCer acts in an autocrine manner to control astrocyte transcriptional programs that promote neurodegeneration. In addition, LacCer in astrocytes controls the recruitment and activation of microglia and CNS-infiltrating monocytes in a non-cell autonomous manner by regulating production of the chemokine CCL2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), respectively. We also detected high B4GALT6 gene expression and LacCer concentrations in CNS MS lesions. Inhibition of LacCer synthesis in mice suppressed local CNS innate immunity and neurodegeneration in EAE and interfered with the activation of human astrocytes in vitro. Thus, B4GALT6 regulates astrocyte activation and is a potential therapeutic target for MS and other neuroinflammatory disorders.
Lactosylceramide is a type of ceramide incorporating lactose. Ceramides are composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells and act as structural elements, ceramide can participate in a variety of cellular signalling. In this study they should that production of lactosylceramide by astrocytes causes astrocytes to produce factors that cause nerve death. They also stimulate microglial and macrophage activity. Inhibition of this target limited nerodegeneration may be this can happen in MS.