Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation

In multiple sclerosis and experimental autoimmune encephalomyelitis, astrocytes produce lactosylceramide, a glycolipid that promotes astrocyte and microglial activation and immune cell infiltration into the CNS. Astrocytes have complex roles in health and disease, thus it is important to study the p...

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Vydáno v:	Nature medicine Ročník 20; číslo 10; s. 1147 - 1156
Hlavní autoři:	Mayo, Lior, Trauger, Sunia A, Blain, Manon, Nadeau, Meghan, Patel, Bonny, Alvarez, Jorge I, Mascanfroni, Ivan D, Yeste, Ada, Kivisäkk, Pia, Kallas, Keith, Ellezam, Benjamin, Bakshi, Rohit, Prat, Alexandre, Antel, Jack P, Weiner, Howard L, Quintana, Francisco J
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.10.2014 Nature Publishing Group
Témata:	13/1 13/106 13/31 13/44 14/63 631/250/262 631/250/38 64/60 82/80 96/95 Analysis Animals Antigens, CD - metabolism Astrocytes Astrocytes - immunology Astrocytes - metabolism Autoimmune diseases Biomedicine Cancer Research Cellular biology Central nervous system Central Nervous System - immunology Central Nervous System - metabolism Central Nervous System - pathology Chemokine CCL2 - genetics Encephalomyelitis, Autoimmune, Experimental - genetics Encephalomyelitis, Autoimmune, Experimental - immunology Encephalomyelitis, Autoimmune, Experimental - metabolism Enzymes Female Galactosyltransferases - genetics Galactosyltransferases - metabolism Gene expression Gene Knockdown Techniques Glial Fibrillary Acidic Protein Glycolipids - metabolism Humans Immunity, Innate Infectious Diseases Inflammation Inflammatory diseases Lactosylceramides - metabolism Lesions Metabolic Diseases Mice Mice, Inbred C57BL Mice, Inbred NOD Mice, Transgenic Molecular Medicine Multiple Sclerosis - genetics Multiple Sclerosis - immunology Multiple Sclerosis - metabolism Nerve Degeneration - genetics Nerve Degeneration - immunology Nerve Degeneration - metabolism Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Nervous system Neurosciences Up-Regulation
ISSN:	1078-8956, 1546-170X, 1546-170X
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Shrnutí:	In multiple sclerosis and experimental autoimmune encephalomyelitis, astrocytes produce lactosylceramide, a glycolipid that promotes astrocyte and microglial activation and immune cell infiltration into the CNS. 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.
Bibliografie:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23
ISSN:	1078-8956 1546-170X 1546-170X
DOI:	10.1038/nm.3681