Format

Send to

Choose Destination
See comment in PubMed Commons below
Nat Med. 2014 Oct;20(10):1147-56. doi: 10.1038/nm.3681. Epub 2014 Sep 14.

Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation.

Author information

1
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2
FAS Center for Systems Biology, Harvard University, Boston, Massachusetts, USA.
3
Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
4
Neuroimmunology Research Lab, Center for Excellence in Neuromics, Department of Neuroscience, University of Montreal, Quebec, Canada.
5
Department of Pathology, University of Montreal and Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.

Abstract

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.

PMID:
25216636
PMCID:
PMC4255949
DOI:
10.1038/nm.3681
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center