Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS.

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.

• Authors: Chun-Cheih Chao, Cristina Gutiérrez-Vázquez, Veit Rothhammer, Lior Mayo, Michael A Wheeler, Emily C Tjon, Stephanie E J Zandee, Manon Blain, Kalil Alves de Lima, Maisa C Takenaka, Julian Avila-Pacheco, Patrick Hewson, Lei Liu, Liliana M Sanmarco, Davis M Borucki, Gabriel Z Lipof, Sunia A Trauger, Clary B Clish, Jack P Antel, Alexandre Prat, Francisco J Quintana
• Journal: Cell (Cell) Vol. 179 Issue 7 Pg. 1483-1498.e22 (12 12 2019) ISSN: 1097-4172 [Electronic] United States
• PMID: 31813625 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• IPS-1 protein, mouse
• NF-kappa B
• 1-Deoxynojirimycin
• Lactic Acid
• miglustat
• Hexokinase
• hexokinase 2, mouse
• Phospholipases A2, Secretory

Topics

• 1-Deoxynojirimycin (analogs & derivatives, pharmacology, therapeutic use)
• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Astrocytes (drug effects, metabolism, pathology)
• Brain (metabolism, pathology)
• Cells, Cultured
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, metabolism)
• Female
• Hexokinase (metabolism)
• Humans
• Lactic Acid (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Phospholipases A2, Secretory (genetics, metabolism)