Involvement of microglia–neuron interactions in the tumor necrosis factor‐α release, microglial activation, and neurodegeneration induced by trimethyltin

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Abstract
Trimethyltin (TMT) is a neurotoxicant known to induce early microglial activation. The present study was undertaken to investigate the role played by these microglial cells in the TMT‐induced neurotoxicity. The effects of TMT were investigated in monolayer cultures of isolated microglia or in neuron‐enriched cultures and in neuron–microglia and astrocyte–microglia cocultures. The end points used were morphological criteria; evaluation of cell death and cell proliferation; and measurements of tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and nitric oxide (NO) release in culture supernatant. The results showed that, in cultures of microglia, TMT (10−6M) caused, after a 5‐day treatment, an increased release of TNF‐α, without affecting microglial shape or cell viability. When microglia were cocultured with astrocytes, TNF‐α release was decreased to undetectable levels. In contrast, in neuron–microglia cocultures, TNF‐α levels were found to increase at lower concentrations of TMT (i.e., 10−8M). Moreover, at 10−6M of TMT, microglia displayed further morphological activation, as suggested by process retraction and by decrease in cell size. No morphological activation was observed in cultures of isolated microglial cells and in astrocyte–microglia cocultures. With regard to neurons, 10−6M of TMT induced about 30% of cell death, when applied to neuron‐enriched cultures, whereas close to 100% of neuronal death was observed in neuron–microglia cocultures. In conclusion, whereas astrocytes may rather dampen the microglial activation by decreasing microglial TNF‐α production, neuronal–microglial interactions lead to enhanced microglial activation. This microglial activation, in turn, exacerbates the neurotoxic effects of TMT. TNF‐α may play a major role in such cell–cell communications.