Expression of excitatory amino acid transporter-2 (EAAT-2) and glutamine synthetase (GS) in brain macrophages and microglia of SIVmac251-infected macaques

Na+-dependent transporters for glutamate (excitatory amino acid transporters, EAATs) clear extracellular glutamate in the brain and prevent excitotoxic neuronal damage. Glutamine synthetase (GS) provides metabolic support for neurones by producing the neurotrophic amino acid glutamine. EAAT and GS expression has recently been demonstrated in macrophages and microglial cells in vitro, and in two models of acute inflammation in vivo. This observation might modify our current understanding of brain inflammation, which considers activated microglia and brain macrophages as the main neurotoxic cells through their production of a variety of neurotoxins, including glutamate. EAAT and GS expression by these cells would entail neuroprotective and neurotrophic properties, counterbalancing the deleterious consequences of microglial activation. Macaque infection by the simian immunodeficiency virus (SIV) is considered the most relevant model for human acquired immunodeficiency syndrome (AIDS), including chronic inflammation of the brain at the early asymptomatic stage of the infection, followed by an AIDS-like disease where neuronal death occurs. We studied the expression of EAAT-2 and GS in the brains of three SIVmac251-infected and two noninfected cynomolgus macaques. We found that both microglia and brain macrophages expressed EAAT-2 and GS in infected primates, suggesting that these cells might, like astrocytes, clear extracellular glutamate and provide glutamine to neurones. Microglia and macrophages could thus have neuroprotective and neurotrophic properties in addition to their production of neurotoxins. This finding might explain the contrast between early intense microglial activation and the late occurrence of neuronal apoptotic cell death, which is mainly observed at the terminal stage of the disease.