Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS.
1-Deoxynojirimycin
/ analogs & derivatives
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Astrocytes
/ drug effects
Brain
/ metabolism
Cells, Cultured
Encephalomyelitis, Autoimmune, Experimental
/ drug therapy
Female
Hexokinase
/ metabolism
Humans
Lactic Acid
/ metabolism
Male
Mice
Mice, Inbred C57BL
NF-kappa B
/ metabolism
Phospholipases A2, Secretory
/ genetics
MAVS
Miglustat
NF-κB
astrocytes
cPLA2
lactate
lactosylceramide
metabolism
multiple sclerosis
neuroinflammation
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
12 12 2019
12 12 2019
Historique:
received:
01
02
2019
revised:
31
07
2019
accepted:
13
11
2019
pubmed:
10
12
2019
medline:
6
6
2020
entrez:
10
12
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31813625
pii: S0092-8674(19)31272-3
doi: 10.1016/j.cell.2019.11.016
pmc: PMC6936326
mid: NIHMS1544731
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
IPS-1 protein, mouse
0
NF-kappa B
0
1-Deoxynojirimycin
19130-96-2
Lactic Acid
33X04XA5AT
miglustat
ADN3S497AZ
Hexokinase
EC 2.7.1.1
hexokinase 2, mouse
EC 2.7.1.1
Phospholipases A2, Secretory
EC 3.1.1.4
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1483-1498.e22Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK040561
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102807
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES025530
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI126880
Pays : United States
Organisme : NINDS NIH HHS
ID : F32 NS101790
Pays : United States
Organisme : NICHD NIH HHS
ID : R24 HD000836
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES029136
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA207021
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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