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: 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
• Journal: Nature medicine (Nat Med) Vol. 20 Issue 10 Pg. 1147-56 (Oct 2014) ISSN: 1546-170X [Electronic] United States
• PMID: 25216636 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Animals
• Antigens, CD (metabolism)
• Astrocytes (immunology, metabolism)
• Central Nervous System (immunology, metabolism, pathology)
• Chemokine CCL2 (genetics)
• Encephalomyelitis, Autoimmune, Experimental (genetics, immunology, metabolism)
• Female
• Galactosyltransferases (genetics, 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, immunology, metabolism)
• Nerve Degeneration (genetics, immunology, metabolism)
• Nerve Tissue Proteins (genetics, metabolism)
• Up-Regulation