2. Academic Validation
  3. Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS

Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS

  • Cell. 2019 Dec 12;179(7):1483-1498.e22. doi: 10.1016/j.cell.2019.11.016.
Chun-Cheih Chao 1,  Cristina Gutiérrez-Vázquez 1,  Veit Rothhammer 2,  Lior Mayo 3,  Michael A Wheeler 1,  Emily C Tjon 1,  Stephanie E J Zandee 4,  Manon Blain 5,  Kalil Alves de Lima 1,  Maisa C Takenaka 1,  Julian Avila-Pacheco 6,  Patrick Hewson 1,  Lei Liu 1,  Liliana M Sanmarco 1,  Davis M Borucki 1,  Gabriel Z Lipof 1,  Sunia A Trauger 7,  Clary B Clish 6,  Jack P Antel 5,  Alexandre Prat 8,  Francisco J Quintana 9
Affiliations

Affiliations

  • 1 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Klinikum Rechts der Isar, Department of Neurology, Technical University of Munich, Ismaninger Str. 22, Munich 81675, Germany.
  • 3 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Cell Research and Immunology, the George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
  • 4 Neuroimmunology Research Lab, CRCHUM and Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montréal, QC H2X 0A9, Canada.
  • 5 Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.
  • 6 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 7 FAS Center for Systems Biology, Harvard University, Boston, MA 02115, USA.
  • 8 Department of Cell Research and Immunology, the George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
  • 9 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: fquintana@rics.bwh.harvard.edu.
PMID: 31813625 DOI: 10.1016/j.cell.2019.11.016
Abstract

Metabolism has been shown to control peripheral immunity, but little is known about its role in central nervous system (CNS) inflammation. Through a combination of proteomic, metabolomic, transcriptomic, and perturbation studies, we found that sphingolipid metabolism in astrocytes triggers the interaction of the C2 domain in cytosolic Phospholipase A2 (cPLA2) with the CARD domain in mitochondrial Antiviral signaling protein (MAVS), boosting NF-κB-driven transcriptional programs that promote CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis. cPLA2 recruitment to MAVS also disrupts MAVS-hexokinase 2 (HK2) interactions, decreasing HK enzymatic activity and the production of lactate involved in the metabolic support of neurons. Miglustat, a drug used to treat Gaucher and Niemann-Pick disease, suppresses astrocyte pathogenic activities and ameliorates EAE. Collectively, these findings define a novel immunometabolic mechanism that drives pro-inflammatory astrocyte activities, outlines a new role for MAVS in CNS inflammation, and identifies candidate targets for therapeutic intervention.

Keywords

MAVS; Miglustat; NF-κB; astrocytes; cPLA2; lactate; lactosylceramide; metabolism; multiple sclerosis; neuroinflammation.

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