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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

351 Scopus citations

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 Î 2-1,4-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.

Original languageEnglish
Pages (from-to)1147-1156
Number of pages10
JournalNature Medicine
Volume20
Issue number10
DOIs
StatePublished - 1 Oct 2014
Externally publishedYes

Funding

FundersFunder number
International Progressive MS Alliance
US National InstitutesFG1941A1/2, AG-043975
National Institutes of HealthR01AG043975, RG4111A1, JF2161-A-5
National Institutes of Health
National Institute of Allergy and Infectious DiseasesR00AI075285
National Institute of Allergy and Infectious Diseases
National Multiple Sclerosis SocietyPA0069
National Multiple Sclerosis Society

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