title: Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation.
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.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lior
authors.initials: L
authors.lastname: Mayo
authors.affiliation: FAS Center for Systems Biology, Harvard University, Boston, Massachusetts, USA.
authors.forename: Sunia A
authors.initials: SA
authors.lastname: Trauger
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Manon
authors.initials: M
authors.lastname: Blain
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Nadeau
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Bonny
authors.initials: B
authors.lastname: Patel
authors.affiliation: Neuroimmunology Research Lab, Center for Excellence in Neuromics, Department of Neuroscience, University of Montreal, Quebec, Canada.
authors.forename: Jorge I
authors.initials: JI
authors.lastname: Alvarez
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Mascanfroni
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ada
authors.initials: A
authors.lastname: Yeste
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Pia
authors.initials: P
authors.lastname: Kivisäkk
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Kallas
authors.affiliation: Department of Pathology, University of Montreal and Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ellezam
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Bakshi
authors.affiliation: Neuroimmunology Research Lab, Center for Excellence in Neuromics, Department of Neuroscience, University of Montreal, Quebec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Jack P
authors.initials: JP
authors.lastname: Antel
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Quintana
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism*; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018932:Chemokine CCL2 / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005904:Glial Fibrillary Acidic Protein; D006017:Glycolipids / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D007790:Lactosylceramides / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D005904:Glial Fibrillary Acidic Protein; D006017:Glycolipids; D007790:Lactosylceramides; D009419:Nerve Tissue Proteins; C528900:glial fibrillary astrocytic protein, mouse; C009744:CDw17 antigen; C587194:B4galt6 protein, mouse; D005700:Galactosyltransferases