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Published on: July 25, 2022
Lithium limits trimethyltin-induced cytotoxicity and proinflammatory response in microglia without affecting the
Cinzia Fabrizi1, Elena Pompili1, Francesca Somma1
1Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University, Rome, Italy.
Abstract:
Trimethyltin (TMT) is a highly toxic molecule present as an environmental contaminant causing neurodegeneration particularly of the limbic system both in humans and in rodents. We recently described the occurrence of impairment in the late stages of autophagy in TMT-intoxicated astrocytes. Here we show that similarly to astrocytes also in microglia, TMT induces the precocious block of autophagy indicated by the accumulation of the autophagosome marker, microtubule associated protein light chain 3. Consistent with autophagy impairment we observe in TMT-treated microglia the accumulation of p62/SQSTM1, a protein specifically degraded through this pathway. Lithium has been proved effective in limiting neurodegenerations and, in particular, in ameliorating symptoms of TMT intoxication in rodents. In our in vitro model, lithium displays a pro-survival and anti-inflammatory action reducing both cell death and the proinflammatory response of TMT-treated microglia. In particular, lithium exerts these activities without reducing TMT-induced accumulation of light chain 3 protein. In fact, the autophagic block imposed by TMT is unaffected by lithium administration. These results are of interest as defects in the execution of autophagy are frequently observed in neurodegenerative diseases and lithium is considered a promising therapeutic agent for these pathologies. Thus, it is relevant that this cation can still maintain its pro-survival and anti-inflammatory role in conditions of autophagy block. Copyright © 2016 John Wiley & Sons, Ltd.
Insights
Trimethyltin (TMT) exposure blocks autophagy in microglia, a key process in neurodegeneration. Lithium treatment offers neuroprotection by reducing cell death and inflammation, even with the autophagy block intact.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Trimethyltin (TMT) is a neurotoxic environmental contaminant causing limbic system degeneration.
- Previous studies identified late-stage autophagy impairment in TMT-intoxicated astrocytes.
- Microglia, crucial immune cells in the brain, are also affected by TMT toxicity.
Purpose of the Study:
- To investigate the impact of TMT on autophagy in microglia.
- To evaluate the therapeutic potential of lithium in TMT-induced neurotoxicity in microglia.
- To determine if lithium's beneficial effects are dependent on restoring autophagy.
Main Methods:
- Utilized an in vitro model of TMT-intoxicated microglia.
- Assessed autophagy flux by measuring microtubule-associated protein light chain 3 (LC3) and p62/SQSTM1 protein levels.
- Evaluated cell viability and inflammatory markers in response to TMT and lithium treatment.
Main Results:
- TMT exposure induced a precocious block in autophagy in microglia, evidenced by LC3 accumulation.
- TMT-treated microglia showed increased p62/SQSTM1 levels, confirming impaired autophagic degradation.
- Lithium demonstrated pro-survival and anti-inflammatory effects in TMT-treated microglia without altering the TMT-induced autophagy block.
Conclusions:
- TMT intoxication disrupts autophagy in both astrocytes and microglia.
- Lithium provides significant neuroprotective benefits against TMT toxicity in microglia.
- Lithium's therapeutic efficacy in neurodegeneration may be independent of its effects on autophagy flux.
