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Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation

Nature Medicine volume 20, pages 1147–1156 (2014)Cite this article

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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.

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Figure 1: B4GALT6 activity in astrocytes controls CNS inflammation and neurodegeneration.
Figure 2: B4GALT6 inhibition suppresses astrocyte activation during EAE.
Figure 3: LacCer produced by B4GALT6 acts in an autocrine manner to boost astrocyte activation.
Figure 4: B4GALT6 regulates Ccl2 transcriptional activity in astrocytes.
Figure 5: B4GALT6 in astrocytes regulates the activation of microglia and CNS-infiltrating monocytes.
Figure 6: B4GALT5, B4GALT6 and LacCer are upregulated in MS lesions.

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Acknowledgements

The authors thank G. Losyev and D. Kozoriz for cell sorting, F. Kirchhoff (University of Saarland) for providing us with GFAP transgenic mice and G.-X. Zhang (Thomas Jefferson University) for the pLenti-GFAP-EGFP-mir30-shAct1 vector. This work was supported by grants AI075285 and AI093903 from the US National Institutes of Health, RG4111A1 and JF2161-A-5 from the National Multiple Sclerosis Society and PA0069 from the International Progressive MS Alliance (F.J.Q.) and US National Institutes Transformative Grant AG-043975 (H.W.L.); L.M. is supported by a postdoctoral fellowship (FG1941A1/2) from National Multiple Sclerosis Society.

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Authors and Affiliations

  1. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Lior Mayo, Meghan Nadeau, Bonny Patel, Ivan D Mascanfroni, Ada Yeste, Pia Kivisäkk, Keith Kallas, Rohit Bakshi, Howard L Weiner & Francisco J Quintana

  2. FAS Center for Systems Biology, Harvard University, Boston, Massachusetts, USA

    Sunia A Trauger

  3. Department of Neurology and Neurosurgery, Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

    Manon Blain & Jack P Antel

  4. Department of Neuroscience, Neuroimmunology Research Lab, Center for Excellence in Neuromics, University of Montreal, Quebec, Canada

    Jorge I Alvarez & Alexandre Prat

  5. Department of Pathology, University of Montreal and Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

    Benjamin Ellezam

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Contributions

L.M., M.N., P.K., A.Y., K.K. and I.D.M. performed in vitro and in vivo experiments with murine systems; S.A.T. measured lipids; J.I.A., B.E. and A.P. provided unique MS samples; J.I.A. and L.M. performed in vitro experiments with human samples; L.M., M.B. and J.P.A. performed experiments with human astrocytes in culture; L.M. and B.P. performed bioinformatics analysis; R.B. contributed to the initial experimental design; L.M., A.P., J.P.A., H.L.W. and F.J.Q. analyzed and interpreted data; L.M. and F.J.Q. wrote the manuscript; F.J.Q. conceived and supervised the study and edited the manuscript.

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Correspondence to Francisco J Quintana.

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Mayo, L., Trauger, S., Blain, M. et al. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med 20, 1147–1156 (2014). https://doi.org/10.1038/nm.3681

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