Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation

Lior Mayo; Sunia A Trauger; Manon Blain; Meghan Nadeau; Bonny Patel; Jorge I Alvarez; Ivan D Mascanfroni; Ada Yeste; Pia Kivisäkk; Keith Kallas; Benjamin Ellezam; Rohit Bakshi; Alexandre Prat; Jack P Antel; Howard L Weiner; Francisco J Quintana

doi:10.1038/nm.3681

Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation

Nat Med. 2014 Oct;20(10):1147-56. doi: 10.1038/nm.3681. Epub 2014 Sep 14.

Authors

Affiliations

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.

PMID: 25216636
PMCID: PMC4255949
DOI: 10.1038/nm.3681

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD / metabolism
Astrocytes / immunology*
Astrocytes / metabolism*
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*
Female
Galactosyltransferases / genetics
Galactosyltransferases / metabolism*
Gene Knockdown Techniques
Glial Fibrillary Acidic Protein
Glycolipids / metabolism*
Humans
Immunity, Innate
Lactosylceramides / metabolism
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Transgenic
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
Up-Regulation

Substances

Antigens, CD
Ccl2 protein, mouse
Chemokine CCL2
Glial Fibrillary Acidic Protein
Glycolipids
Lactosylceramides
Nerve Tissue Proteins
glial fibrillary astrocytic protein, mouse
CDw17 antigen
B4galt6 protein, mouse
Galactosyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding