The glutamate-glutamine cycle as an inducible, protective face of macrophage activation.
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.
Gras
Gabriel
G
CEA, DSV, DRM, SNV, UMR E-01 Université Paris-Sud XI, Laboratoire de Neuro-Immuno-Virologie, F92265 Fontenay-aux Roses, France. gabriel.gras@cea.fr
Porcheray
Fabrice
F
Samah
Boubekeur
B
Leone
Cathie
C
D000818:Animals; D001921:Brain / Q000166:cytology / Q000276:immunology; D018698:Glutamic Acid / Q000494:pharmacology / Q000502:physiology*; D005973:Glutamine / Q000494:pharmacology / Q000502:physiology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008826:Microbial Sensitivity Tests; D018448:Models, Immunological; D013329:Structure-Activity Relationship
D005973:Glutamine; D018698:Glutamic Acid