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...

Full description

Saved in:
Bibliographic Details
Published in:Nature medicine Vol. 20; no. 10; pp. 1147 - 1156
Main Authors: 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
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.10.2014
Nature Publishing Group
Subjects:
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
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography: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