Na+-dependent high-affinity glutamate transport in macrophages

Excessive accumulation of glutamate in the CNS leads to excitotoxic neurona l damage. However, glutamate clearance is essentially mediated by astrocyte s through Na+-dependent high-affinity glutamate transporters (excitatory am ino acid transporters (EAATs)), Nevertheless, EAAT function was recently sh own to be developmentally restricted in astrocytes and undetectable in matu re astrocytes. This suggests a need for other cell types for clearing gluta mate in the brain. As blood monocytes infiltrate the CNS in traumatic or in flammatory conditions, we addressed the question of,whether macrophages exp ressed EAATs and were involved in glutamate clearance. We found that macrop hages derived from human blood monocytes express both the cystine/glutamate antiporter and EAATs, Kinetic parameters were similar to those determined for neonatal astrocytes and embryonic neurons. Freshly sorted tissue macrop hages did not possess EAATs, whereas cultured human spleen macrophages and cultured neonatal murine microglia did. Moreover, blood monocytes did not t ransport glutamate, but their stimulation with TNF-alpha led to functional transport. This suggests that the acquisition of these transporters by macr ophages could be under the control of inflammatory molecules. Also, monocyt e-derived macrophages overcame glutamate toxicity in neuron cultures by cle aring this molecule. This suggests that brain-infiltrated macrophages and r esident microglia may acquire EAATs and, along with astrocytes, regulate ex tracellular glutamate concentration. Moreover, we showed that EAATs are inv olved in the regulation of glutathione synthesis by providing intracellular glutamate, These observations thus offer new insight into the role of macr ophages in excitotoxicity and in their response to oxidative stress.