Dataset Information

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-?B-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.

SUBMITTER: Chao CC

PROVIDER: S-EPMC6936326 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS.

Chao Chun-Cheih CC Gutiérrez-Vázquez Cristina C Rothhammer Veit V Mayo Lior L Wheeler Michael A MA Tjon Emily C EC Zandee Stephanie E J SEJ Blain Manon M de Lima Kalil Alves KA Takenaka Maisa C MC Avila-Pacheco Julian J Hewson Patrick P Liu Lei L Sanmarco Liliana M LM Borucki Davis M DM Lipof Gabriel Z GZ Trauger Sunia A SA Clish Clary B CB Antel Jack P JP Prat Alexandre A Quintana Francisco J FJ

Cell 20191205 7

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 ...[more]

PMID: 31813625

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Project description:Ross River virus (RRV) is a mosquito-borne alphavirus that causes epidemics of debilitating musculoskeletal disease. To define the innate immune mechanisms that mediate control of RRV infection, we studied a RRV strain encoding 6 nonsynonymous mutations in nsP1 (RRV-T48-nsP16M) that is attenuated in wild-type (WT) mice and Rag1-/- mice, which are unable to mount adaptive immune responses, but not in mice that lack the capacity to respond to type I interferon (IFN) (Ifnar1-/- mice). Utilizing this attenuated strain, our prior studies revealed that mitochondrial antiviral signaling (MAVS)-dependent production of type I IFN by Ly6Chi monocytes is critical for control of acute RRV infection. Here, we infected Mavs-/- mice with either WT RRV or RRV-T48-nsP16M to elucidate MAVS-independent protective mechanisms. Mavs-/- mice infected with WT RRV developed severe disease and succumbed to infection, whereas those infected with RRV-T48-nsP16M exhibited minimal disease signs. Mavs-/- mice infected with RRV-T48-nsP16M had higher levels of systemic type I IFN than Mavs-/- mice infected with WT virus, and treatment of Mavs-/- mice infected with the attenuated nsP1 mutant virus with an IFNAR1-blocking antibody resulted in a lethal infection. In vitro, type I IFN expression was induced in plasmacytoid dendritic cells (pDCs) cocultured with RRV-infected cells in a MAVS-independent manner, and depletion of pDCs in Mavs-/- mice resulted in increased viral burdens in joint and muscle tissues, suggesting that pDCs are a source of the protective IFN in Mavs-/- mice. These data suggest that pDC production of type I IFN through a MAVS-independent pathway contributes to control of RRV infection.IMPORTANCE Arthritogenic alphaviruses, including Ross River virus (RRV), are human pathogens that cause debilitating acute and chronic musculoskeletal disease and are a significant public health burden. Using an attenuated RRV with enhanced susceptibility to host innate immune responses has revealed key cellular and molecular mechanisms that can mediate control of attenuated RRV infection and that are evaded by more virulent RRV strains. In this study, we found that pDCs contribute to the protective type I interferon response during RRV infection through a mechanism that is independent of the mitochondrial antiviral signaling (MAVS) adaptor protein. These findings highlight a key innate immune mechanism that contributes to control of alphavirus infections.

Dataset Information

Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS.

Publications

Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS.

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