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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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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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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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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DOI: https://doi.org/10.1038/nm.3681
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