Originally published online as doi:10.1189/jlb.0306153 on August 15, 2006
Published online before print August 15, 2006
(Journal of Leukocyte Biology. 2006;80:1067-1075.)
© 2006
by Society for Leukocyte Biology
The glutamate-glutamine cycle as an inducible, protective face of macrophage activation
Gabriel Gras1,
Fabrice Porcheray,
Boubekeur Samah and
Cathie Leone
CEA, DSV, DRM, SNV, UMR E-01 Université Paris-Sud XI, CRSSA, IFR13 Institut Paris Sud Cytokines, Laboratoire de Neuro-Immuno-Virologie, Fontenay-aux Roses, France
1 Correspondence: Laboratoire de Neuro-Immuno-Virologie, Service de Neurovirologie UMR E-01, CEA DSV/DRM, 18, route du Panorama, BP6, F92265 Fontenay-aux Roses, France. E-mail: gabriel.gras{at}cea.fr
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ABSTRACT
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Neuronal damage in HIV infection results mainly from chronic activation of brain tissue and involves inflammation, oxidative stress, and glutamate-related neurotoxicity. Glutamate toxicity acts via two distinct pathways: an excitotoxic one, in which glutamate receptors are hyperactivated, and an oxidative one, in which cystine uptake is inhibited, resulting in glutathione depletion, oxidative stress, and cell degeneration. A number of studies have shown that astrocytes normally take up glutamate, keeping extracellular glutamate concentration low in the brain and preventing excitotoxicity. They, in turn, provide the trophic amino acid glutamine via their expression of glutamine synthetase. These protective and trophic actions are inhibited in HIV infection, probably as a result of the effects of inflammatory mediators and viral proteins. In vitro and in vivo studies have demonstrated that activated microglia and brain macrophages (AMM) express the transporters and enzymes of the glutamate cycle. This suggests that in addition to their recognized neurotoxic properties in HIV infection, these cells exhibit some neuroprotective properties, which may partly compensate for the inhibited astrocytic function. This hypothesis might explain the discrepancy between microglial activation, which occurs early in the disease, and neuronal apoptosis and neuronal loss, which are late events. In this review, we discuss the possible neuroprotective and neurotrophic roles of AMM and their relationships with inflammation and oxidative stress.
Key Words: inflammation • neuroprotection • neurotoxicity • AIDS • TSE • microglia
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INTRODUCTION
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Chronic activation of CNS mononuclear phagocytes (MP), namely macrophages and microglial cells, plays a key role in HIV-induced neurotoxicity. Indeed, indirect mechanisms, where immune activation leads MP to produce neurotoxins and repress astroglial protective properties, are now broadly accepted as the main path to HIV-induced neurotoxicity, although a variety of studies also pointed to direct effects of viral proteins. The mechanism of neuronal damage is not fully understood but involves glutamate-related excitotoxicity and oxidative stress, resulting in neuronal apoptosis (for reviews, see refs. [1
2
3
]). Excitotoxicity is not specific for HIV infection and is shared by many other acute and chronic neurological diseases (for review, see ref. [4
]). Nevertheless, in vitro and in vivo studies have now shown that activated macrophages and microglial cells (AMM) do express high-affinity glutamate transporters and glutamine synthetase (GS) in a variety of pathological situations, including acute and chronic CNS inflammation. As a result of this inducible expression of the astroglial effectors of protection, MP might, at least in part, compensate for the deleterious face of their activation. This hypothesis may explain the gap between microglial activation, which is progressive in HIV infection [5
, 6
], and neuronal damage, which occurs late (for review, see ref. [7
]). The present review will focus on in vitro and in vivo data, which suggest a neuroprotective face of macrophages/microglia activation through the setting-up of glutamate clearance and subsequent antioxidant properties.
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THE GLUTAMATE-GLUTAMINE CYCLE IN THE CNS
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Glutamate is the main excitatory neurotransmitter in the CNS [8
]. It is released from glutamatergic neuronal vesicles through a calcium-dependent mechanism (for review, see ref. [9
]). Its concentration in the synaptic cleft must be kept in the micromolar range [10
], as high or sustained glutamate receptor activation may induce neuronal death [11
, 12
] via calcium and/or sodium deregulation, a mechanism called excitotoxicity. Glutamate concentration in glial cell is in the millimolar range and reaches 200 mM in synaptic vesicles [13
]. Glutamate concentration thus needs a tight control, which requires an energy supply to maintain its gradient.
A family of transporter proteins, excitatory amino acid transporters (EAAT), regulates extracellular concentration of glutamate. To date, these include five cloned subtypes[14
15
16
17
18
19
]. The three first EAAT were primarily cloned in murine systems before their human homologues were characterized, and EAAT-4 and EAAT-5 were first described in human. EAAT-1 and EAAT-2 were primarily observed in astrocytes, EAAT-3 is a neuronal transporter with a somatodendritic location [20
], and EAAT-4 is expressed in the cerebellum [18
] and EAAT-5 in the retina [19
]. These transporters use the Na+ and K+ electrochemical gradients as a driving force to take up extracellular glutamate against a several thousand-fold concentration gradient, leading to an extracellular concentration below 1 µM and ensuring a high signal-to-noise ratio for glutamate receptors (for review, see ref. [21
]). EAAT gene knockout experiments in mice show that the astroglial transporters EAAT-1 and EAAT-2 are essential for protection against excitotoxicity, by clearing extracellular glutamate, whereas the neuronal transporter EAAT-3 is not [22
, 23
].
Astrocytes are the main protectors of neurons from excitotoxicity in the normal CNS, and this protection is conferred by clearance of extracellular glutamate. At the same time, the extracellular glutamate level is proportional to intracellular glutamate concentration (for review, see ref. [24
]), and glutamate metabolism within glutamate-scavenging cells is vital to prevent excitotoxicity. Glutamate is converted rapidly into glutamine by GS, an astrocyte-expressed enzyme [25
, 26
] localized in the immediate vicinity of glutamatergic synapses [27
28
29
30
31
]. GS is a critical component of astrocyte neuroprotective and neurotrophic properties.
Glutamine is secreted by astrocytes through system N [32
, 33
] and/or ASCT2 transporters [34
]. SN1, the cloned transporter that mediates system N transport, is a transmembrane protein with 11 putative transmembrane domains [32
]. It is expressed by astrocytes and mediates glutamine uptake as well as glutamine efflux from glial cells. Its high dependence on the proton gradient may explain the coupling of system N-mediated glutamine efflux to synaptic activity, when the extracellular milieu is acidified. Conversely, the ASCT2 transporter (system ASC) bears eight putative transmembrane domains [34
]. Glutamine efflux via ASCT2 is dependent on an opposite flux of amino acid counter-substrate (exchange for alanine, serine, or cystein) but is not dependent on pH. Its pattern of expression suggests that ASCT2 intervenes in situations where astrocytes proliferate (e.g., reactive astrogliosis, glioma, developing brain). Glutamine uptake into neurons occurs through the system A transport system. SAT1/GlnT, a pH-sensitive transporter with 11 putative transmembrane domains, ensures this function [35
].
This coupling of GS and glutamine traffic from glia to neurons permits glutamate passage in the extracellular compartment in a non-neuroactive form (glutamine), thus avoiding toxicity (for review, see ref. [36
]). Neurons then hydrolyze glutamine into glutamate and ammonia via the mitochondrial phosphate-dependent glutaminase (for review, see ref. [37
]) and store glutamate in vesicles by using the vesicular glutamate transporters (VGLUT) [38
, 39
]. This scheme is illustrated in Figure 1
.
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AMM-PRODUCING NEUROTOXINS ACT MAINLY THROUGH GLUTAMATE RECEPTOR ACTIVATION
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It has long been observed that activation of microglia leads to the secretion of N-methyl-D-aspartate (NMDA) receptor-activating substances, able to cause excitotoxicity [40
, 41
], including glutamate itself [42
43
44
]. Likewise, monocytes/macrophages also secrete NMDA receptor agonists in response to immune stimulation [45
46
47
]. Nevertheless, glutamate itself may only account for 30% of NMDA receptor stimulation by stimulated macrophage secretory products [47
], suggesting that other agonists must be produced. The consequences of macrophage/microglial immune activation for neuron survival are not so clear [40
]. Indeed, LPS treatment did not induce glutamate overproduction in a series of 11 macrophage conditioned media (MCM), induced neurotoxicity in only one such MCM, and even provided enhanced neuron viability in two others [48
].
Viral proteins produced by HIV-infected macrophages and microglia also act at the NMDA receptor level, but these are not the purpose of this review. Nevertheless, beside viral toxins, HIV replication in MP also leads to the production of glutamate and MK-801-sensitive toxicity [48
49
50
]. This production of glutamate in infected MP cultures is glutamine-dependent, as it is linked to an increase in phosphate-dependent mitochondrial glutaminase release in the extracellular milieu [51
]. Of note, the release of glutaminase seems a consequence of HIV-induced cell death in macrophages, with a clear relation between glutaminase release and glutamate concentration on one hand and the level of RT activity and the concomitant drop in cell viability on the other [51
].
Finally, although the relative contribution of each secretory product is still a matter of study, it is now clear that activated and/or infected MP produce a variety of molecules that activate the NMDA receptor or modulate its sensitivity. Among these, neurotrophins, cytokines, serine proteases, kynurenins, and glycine may be relevant [52
53
54
55
56
57
58
59
60
]. Whether this property of immunocompetent macrophages/microglia, i.e., activation and facilitation of the glutamatergic transmission, leads to excitotoxicity in pathological conditions is not yet well-defined, and mechanisms to limit such a definitive, deleterious consequence of an otherwise benefical physiological activity may exist.
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AMM EXPRESS THE MOLECULAR EFFECTORS OF THE GLIAL GLUTAMATE-GLUTAMINE CYCLE IN VITRO AND IN VIVO
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Primary murine microglia [61
62
63
64
65
], as well as simian resident spleen macrophages and human monocyte-derived macrophages (MDM) [62
], express the two main glial high-affinity glutamate transporters, EAAT-1 and -2, when activated. Macrophages and microglial cells also express GS in the rat [66
] and in SIV-infected macaques [67
], as well as in our in vitro model of human MDM [68
]. Coexpression of EAAT and GS is striking, as astrocyte neuroprotective properties are associated with the very same expression pattern.
This expression contrasts with its absence in physiological conditions as assessed in the rat [69
], and it was this observation that led investigators to consider astrocytes alone as potential effectors of the glutamate-glutamine cycle. The regulation features in astrocytes and MP may thus be totally different, with constitutive expression of EAAT and GS in astrocytes and an inducible profile in MP. Accordingly, EAAT expression by human MDM is highly dependent on cell activation and differentiation in vitro [62
, 68
]. This suggests a compensatory mechanism that would limit or counteract some deleterious consequences of MP activation in the brain.
A differential expression pattern of glutamate transporters and GS is also found in a number of disease conditions. Neuropathological examinations have shown that brain MP express EAAT-2 and GS in asymptomatic SIVmac251-infected macaques, whereas those from uninfected animals do not [67
]. Of note, most perineuronal microglia strongly express EAAT-2 and GS in this model of human HIV infection. Likewise, in a study with 12 HIV-infected humans at different stages of the disease and three HIV-negative controls, EAAT-1 expression by AMM increased with the disease stage in the white matter, whereas it was strong in perineuronal microglia only in subjects without HIV encephalitis [70
]. The picture is quite different in human transmissible spongiform encephalopathies (TSE), diseases that allow a profound but atypical microglial activation, with little proinflammatory cytokine expression if any [71
, 72
]. Indeed, in a series of 18 cases, including eight sporadic Creutzfeldt-Jakob disease (CJD), two iatrogenic CJD, two familial CJD, two variant CJD, and four fatal familial insomnia, EAAT-1 expression in AMM was detected [73
] but remained far lower than that which we observed in human AIDS [70
]. Moreover, the only correlate to the EAAT-1 expression level in TSE was disease duration. This suggests that contrary to what we observed in AIDS, neuronal death precedes AMM expression of EAAT, which clearly occurs only in long-lasting cases. This difference in EAAT expression in neuro-AIDS versus TSE may suggest specific regulation of EAAT expression in AMM, depending on the activation pathway. Indeed, macrophages but also microglia undergo anti-inflammatory activation upon apoptotic cell ingestion (for review, see ref. [74
]), and we recently showed that such orientation in macrophage activation is plastic and reversible [75
]. Such mechanisms may explain why some AMM express EAAT and GS (in HIV patients), and others do not express it at all or express it weakly (as in TSE cases). Indeed, AMM in AIDS exhibit proinflammatory properties, and AMM in TSE appear to be anti-inflammatory, as suggested by the pre-existence of neuronal death and the scarce IL-1ß expression [71
, 72
].
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GLUTAMATE METABOLISM AND OXIDATIVE STRESS ARE CLOSELY RELATED
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The tripeptide glutathione (GSH; 
-glutamyl-cysteinyl-glycine) is the main cellular antioxidant. It is critical to brain protection, which contributes to 20% of oxygen consumption. GSH-mediated reduction of radicals and peroxides does not use up GSH, but its role in xenobiotic detoxification, in cytosolic protein sulhydryl group reduction, and in its export from the cell causes GSH depletion and requires efficient GSH synthesis for replacement (for review, see ref. [76
]). The limiting extracellular substrate for GSH synthesis is cystein or its oxidized form cystine. Glutamate and GSH metabolisms intricately interact as a result of complex competition features for transporter use, and these interactions may not be the same in MP, astrocytes, and neurons.
In macrophages, cystine is taken up through the sodium-independent, CD98/xCT cystine-glutamate antiporter (xc-transport) [77
] and not (or in scarcely quantifiable amounts) through EAAT. The cystine-glutamate antiporter exchanges extracellular cystine for intracellular glutamate secretion [78
], a reaction that may occur in either direction. As a consequence, extracellular cystine and glutamate compete on the cystine-glutamate antiporter [79
, 80
]. The intracellular glutamate pool is dynamic [81
, 82
] and is depleted rapidly when extracellular cystine is in excess [81
]. In such conditions, intracellular glutamate therefore becomes unavailable as a GSH precursor, and secreted glutamate may inhibit cystine uptake competitively [81
], further inducing GSH depletion. Conversely, cystine starvation or oxidative stress (exposure to NO or peroxinitrite) depletes GSH and induces an adaptive response with increased cystine uptake [83
84
85
], a mechanism that may accelerate depletion of the glutamate pool. In many cell types, an excess of extracellular glutamate inhibits cystine uptake, leading to cell degeneration and death. This nonexcitotoxic mechanism of glutamate toxicity is called oxidative glutamate toxicity [79
, 80
, 86
87
88
89
90
91
92
93
]. In this context, EAAT-mediated glutamate uptake enables a high glutamate concentration gradient to be maintained through the cell membrane, even if extracellular glutamate concentration rises. This gradient stimulates the xc-system and leads to enhanced cystine uptake and GSH synthesis, although competition for uptake occurs. This mechanism has been demonstrated in Müller cells [94
] and macrophages [77
].
The situation is different for neurones, which lack the xc-system and cannot exchange cystine for glutamate. In fact, EAAT themselves can serve as cystine and cystein transporters, adding complexicity to the picture. Zerangue and Kavanaugh [95
] described this activity of EAAT in Xenopus oocytes, Bender et al. [96
] in neonatal astrocytes, and Flynn and McBean [97
, 98
] in synaptosomes. EAAT-1, EAAT-2, and EAAT-3 transport cystine and cystein, with tenfold greater Vmax values for cystein [99
]. This transport is inhibitable by glutamate, and competition for the transporter thus occurs. Among EAAT, EAAT-3 is the most effective for cystein capture [95
, 99
], consistent with the recent study of Aoyama et al. [100
], showing that this transporter is critical to GSH synthesis in neurons. GSH secreted from astrocytes is cleaved to form cysteinylglycine [101
], a substrate for the aminopeptidase N located on the neurone surface [102
], releasing cystein, which is then taken up by EAAT-3 for insertion into the GSH synthesis chain [100
]. This scheme of transporter use for GSH synthesis is illustrated in Figure 2
.
Another example of the intimate links between glutamate transport and the oxidative stress mechanism is that oxidative metabolism regulates EAAT function directly [103
104
105
106
]. Vanoni et al. [107
] showed in a mouse model of amyotrophic lateral sclerosis that the murine counterpart of EAAT-2, glutamate transporter 1 (GLT-1), exhibits increased internalization and degradation through aberrant oxidative stress [expression of a mutant superoxide dismutase 1 (SOD1) gene], whereas the other glutamate transporters are not affected. Of note, wild-type SOD1 expression also inhibits GLT-1 transport but without leading to its degradation. In addition to transporter degradation, mediators of oxidative stress inhibit EAAT functions through a SH sensor-based mechanism [106
].
In HIV infection, stigmata of oxidative stress are found in brain tissue and in the cerebrospinal fluid [108
, 109
]. This may relate to the excess of glutamate found in the CSF of patients with HIV dementia [110
] as well as the limited but long-lasting increase in glutamate content in the brains of SIV-infected macaques [111
]. From this point of view, macrophages may exhibit specific adaptation to oxidative stress compared with other cell types. For example, endogenous NO° production does not deplete GSH in RAW264.7 murine macrophages [112
], suggesting that AMM may be less sensitive to oxygen radicals and perhaps, maintain a protective EAAT and GS expression in the infected brain.
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POTENTIAL NEUROPROTECTIVE ROLE OF MACROPHAGES: IS THE INFLAMMATION-ANTI-INFLAMMATION BALANCE A KEY?
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Several in vitro studies have shown that EAAT expression and function in astrocytes are reduced by HIV, probably as a result of the effects of inflammatory mediators and viral proteins [113
114
115
116
117
118
]. As the capacity of glutamate clearance by macrophages is a recently discovered feature, most studies focused on the astrocytes. Inflammation is a hallmark of CNS infection by HIV and is mediated by AMM-secreted cytokines, mainly TNF-
and IL-1ß. Of these cytokines, TNF- inhibits astrocyte clearance of glutamate [114
] and decreases EAAT-2 expression in these cells [119
]. Alternatively, IL-ß enhances the positive effect of PGE2 [120
]. The inhibitory effect of TNF- may depend on the newly identified, astrocyte-expressed gene AEG2, which affects EAAT-2 [121
].
TNF- has different effects on macrophages and microglia. First, it induces EAAT function in differentiating monocytes [62
]. Conversely, TNF- induced in murine microglia by LPS [122
, 123
] (but also by glutamate itself) [124
] increases EAAT-2 expression and function, leading to neuronal protection in vitro. Likewise, LPS and TNF- also increase EAAT expression and function in human MDM [68
]. The precise influence of TNF- on neuronal survival outcome in neuroinflammatory conditions is thus not entirely clear and deserves further investigation. IFN- also limits excitotoxicity and increases glutamate transporter expression in AMM [125
]. Thus, the inflammation that develops early after CNS infection may favor a neuroprotective face of microglial activation and decrease these properties in astrocytes. In addition to these recent data about inflammatory mediator action, few studies are available about the putative involvement of anti-inflammatory molecules. Jacobsson et al. [122
] found that corticosterone inhibits EAAT-2 expression and function in murine microglia, probably by inhibiting the positive autocrine action of TNF-. Likewise, corticosterone decreased glutamate clearance capacity in hippocampal glial cultures [126
], which suggests deleterious activities of anti-inflammation from this point of view. Nevertheless, one should not forget that the inhibition of oxidative stress by anti-inflammatory molecules may also help in normalizing glutamate metabolism. Moreover, in our model of human MDM, dexamethasone is the most potent inducer of EAAT-1 gene expression and weakly induces glutamate uptake [68
]. This difference between human MDM and murine microglia may respond to differences in TNF- sensitivity, as our MDM do not secrete detectable TNF- when differentiated.
Taken together, these data suggest that the balance between inflammation and anti-inflammation may indeed modulate macrophage and microglial cell properties toward glutamate metabolism, but not unequivocally, and much still remains to be learned about these aspects of microglial activation. The possible protective and damaging mechanisms of macrophage activation during HIV infection are schematized in Figure 3
.
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Figure 3. Possible protective and/or damaging mechanisms of macrophage activation during HIV-1 infection. (1) The chronic inflammation set-up in the infected brain leads to the overproduction of a variety of inflammatory mediators such as kynurenins, eicosanoids, NO, platelet-activation factor, and TNF. These molecules sustain microgliosis and astrogliosis. They may also have opposite effects on neuron survival. Nevertheless, their action on NMDA receptor leads to excitotoxicity via direct activation or receptor hypersensitization. These molecules also modulate the capacity of astrocytes (repression) and MP (variable effect) to clear and metabolize glutamate. (2) The regulation of extracellular glutamate concentration is disturbed as a result of enhanced secretion of glutaminase by infected MP, increased production by activated astrocytes, and regulated clearance and metabolism. The increase is weak during asymptomatic infection but may reach high excess during encephalitis and dementia. Although it has long been shown that viral proteins and inflammatory mediators repress astrocyte capacity to clear glutamate, the balancing effect of MP infection and activation is not yet known. (3) Viral proteins such as Tat, gp120, and Vpr possess direct toxicity, notably via the NMDA receptor. In addition to their glial activation properties that may participate in gliosis onset, they repress astrocyte ability to clear glutamate. Their effect on MP-inducible glutamate metabolism is not yet characterized, but HIV replication decreases glutamate uptake by MP. (4) Gliosis and MP infection also lead to the production of a variety of neuroprotective factors, which may compensate for the deleterious aspects of brain inflammation.
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In conclusion, it is now clear that beside astrocytes, brain macrophages and microglial cells constitute a local, inducible cell population for glutamate clearance and metabolism, available on demand. This property may be critical to neuronal survival outcome in brain inflammation in general and in HIV encephalopathy in particular. Of interest, the differences that exist between EAAT regulation in astrocytes and AMM may open new perspectives for designing neuroprotective treatments. The availability of the EAAT-2 gene promoter [127
] may help in achieving this goal.
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ACKNOWLEDGEMENTS
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This laboratory is supported by grants from the "Agence Nationale de Recherche sur le SIDA" (ANRS) and "Ensemble Contre le SIDA" (Sidaction) and recurrent funds of the "Commissariat à l’Energie Atomique" (CEA). F. P., B. S., and C. L. hold doctoral fellowships from the ANRS. F. P. was a recipient of a fellowship from the "Fondation pour la Recherche Médicale" (FRM). We warmly thank Dr. Ann Mullally for kindly correcting the manuscript.
Received March 4, 2006;
revised May 4, 2006;
accepted May 5, 2006.
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