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EAAT expression by macrophages and microglia: still more questions than answers

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Abstract

Glutamate is the main excitatory amino acid, but its presence in the extracellular milieu has deleterious consequences. It may induce excitotoxicity and also compete with cystine for the use of the cystine–glutamate exchanger, blocking glutathione neosynthesis and inducing an oxidative stress-induced cell death. Both mechanisms are critical in the brain where up to 20% of total body oxygen consumption occurs. In normal conditions, the astrocytes ensure that extracellular concentration of glutamate is kept in the micromolar range, thanks to their coexpression of high-affinity glutamate transporters (EAATs) and glutamine synthetase (GS). Their protective function is nevertheless sensitive to situations such as oxidative stress or inflammatory processes. On the other hand, macrophages and microglia do not express EAATs and GS in physiological conditions and are the principal effector cells of brain inflammation. Since the late 1990s, a number of studies have now shown that both microglia and macrophages display inducible EAAT and GS expression, but the precise significance of this still remains poorly understood. Brain macrophages and microglia are sister cells but yet display differences. Both are highly sensitive to their microenvironment and can perform a variety of functions that may oppose each other. However, in the very particular environment of the healthy brain, they are maintained in a repressed state. The aim of this review is to present the current state of knowledge on brain macrophages and microglial cells activation, in order to help clarify their role in the regulation of glutamate under pathological conditions as well as its outcome.

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Abbreviations

AD:

Alzheimer’s disease

AEG:

Astrocyte elevated gene

BBB:

Blood–brain barrier

CD:

Cluster of differentiation

CNS:

Central nervous system

CCR:

Chemokine (C-C motif) receptor

CX3CL:

Chemokine (C-X3-C motif) ligand

CX3CR:

Chemokine (C-X3-C motif) receptor

EAAT:

Excitatory amino acid transporter

EGF:

Epidermal growth factor

FGF:

Fibroblast growth factor

FIZZ1:

Found in Inflammatory Zone 1, a marker of alternative activation in murine macrophages

GS:

Glutamine synthetase

GSH:

l-γ-Glutamyl-l-cysteinyl-glycine (glutathione)

GSSG:

Oxidised form of glutathione

HIV:

Human immunodeficiency virus

IFN:

Interferon

IL:

Interleukin

ITIM:

Immunoreceptor tyrosine-based inhibition motif

MDM:

Monocyte-derived macrophages

mGluR:

Metabotropic glutamate receptors

MHC:

Major histocompatibility complex

NF-κB:

Nuclear factor-κB.

PDGF:

Platelet-derived growth factor

PG:

Prostaglandin

SIRPα:

Signal-regulatory protein α

SIV:

Simian immunodeficiency virus

TGF:

Transforming growth factor

TNF:

Tumour necrosis factor

TREM2:

Triggering receptor expressed on myeloid cells 2

VGLUT:

Vesicular glutamate transporter

xCT:

Light chain subunit of the x −c cystine/glutamate exchanger

Ym1:

A heparin-binding lectin, a marker of alternative activation in murine macrophages

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Acknowledgments

The work was supported by the National Agency for Research against AIDS and Viral Hepatitis (ANRS) and the Fondation pour la Recherche Médicale (FRM), as well as funding by the Atomic Energy Commission (CEA).

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  1. Division of Immuno-Virology, Institute of Emerging Diseases and Innovative Therapies, UMR E1 CEA DSV/IMETI/SIV and University Paris South-Paris 11, 18, route du Panorama, 92265, Fontenay-aux Roses, France

    Gabriel Gras, Boubekeur Samah, Audrey Hubert, Cathie Léone, Fabrice Porcheray & Anne-Cécile Rimaniol

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  1. Gabriel Gras
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  2. Boubekeur Samah
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  3. Audrey Hubert
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  4. Cathie Léone
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  5. Fabrice Porcheray
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  6. Anne-Cécile Rimaniol
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Correspondence to Gabriel Gras.

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Gras, G., Samah, B., Hubert, A. et al. EAAT expression by macrophages and microglia: still more questions than answers. Amino Acids 42, 221–229 (2012). https://doi.org/10.1007/s00726-011-0866-6

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  • DOI: https://doi.org/10.1007/s00726-011-0866-6

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