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Microglia as a Surrogate Biosensor to Determine Nanoparticle Neurotoxicity
Published on: October 25, 2016
Involvement of microglia-neuron interactions in the tumor necrosis factor-alpha release, microglial activation, and
C Eskes1, L Juillerat-Jeanneret, G Leuba
1Institute of Physiology, CHUV, Lausanne, Switzerland.
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-alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO) release in culture supernatant. The results showed that, in cultures of microglia, TMT (10(-6) M) caused, after a 5-day treatment, an increased release of TNF-alpha, without affecting microglial shape or cell viability. When microglia were cocultured with astrocytes, TNF-alpha release was decreased to undetectable levels. In contrast, in neuron-microglia cocultures, TNF-alpha levels were found to increase at lower concentrations of TMT (i.e., 10(-8) M). Moreover, at 10(-6) M 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(-6) M 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-alpha production, neuronal-microglial interactions lead to enhanced microglial activation. This microglial activation, in turn, exacerbates the neurotoxic effects of TMT. TNF-alpha may play a major role in such cell-cell communications.
Insights
Trimethyltin (TMT) neurotoxicity is worsened by interactions between neurons and microglia. Microglia activation, driven by TMT, increases neuronal death, while astrocytes may reduce this inflammatory response.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Trimethyltin (TMT) is a known neurotoxicant that triggers early microglial activation.
- Microglia, the brain's resident immune cells, play a critical role in neuroinflammation and neurotoxicity.
- Understanding the precise role of microglia in TMT-induced neurotoxicity is crucial for developing targeted interventions.
Purpose of the Study:
- To investigate the specific role of microglial cells in trimethyltin (TMT)-induced neurotoxicity.
- To examine how neuron-microglia and astrocyte-microglia interactions influence TMT's effects on neuronal and microglial cells.
- To determine the involvement of inflammatory mediators like TNF-alpha in TMT neurotoxicity.
Main Methods:
- Utilized primary cultures of isolated microglia, neuron-enriched cultures, and co-cultures of neuron-microglia and astrocyte-microglia.
- Assessed TMT effects using morphological criteria, cell death and proliferation assays, and measurements of TNF-alpha, IL-6, and NO release.
- Investigated TMT effects at varying concentrations (10(-6) M and 10(-8) M).
Main Results:
- TMT (10(-6) M) increased TNF-alpha release from isolated microglia but did not alter morphology or viability.
- In neuron-microglia co-cultures, TMT (10(-8) M) elevated TNF-alpha levels, and at 10(-6) M, induced microglial morphological activation and nearly 100% neuronal death.
- Astrocytes reduced TMT-induced TNF-alpha release, while neuron-microglia interactions exacerbated TMT neurotoxicity.
Conclusions:
- Astrocytes appear to dampen microglial activation and associated neuroinflammation by reducing TNF-alpha production.
- Interactions between neurons and microglia significantly enhance microglial activation in response to TMT.
- This enhanced microglial activation critically contributes to the exacerbation of TMT-induced neurotoxicity, with TNF-alpha playing a key role in cell communication.
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