Role of zinc in the induction of neurotoxic A1 astrocyte in primary mouse astrocyte culture

Abstract

Neurotoxic A1 astrocyte is induced by microglia-mediated neuroinflammation and plays a critical role in the neuronal damages in various neurological diseases. Therefore, factors facilitating or blocking the conversion to A1 astrocyte can be promising therapeutic targets. In this study, we demonstrate that treatment with 30μM zinc chloride converted normal astrocytes to A1 astrocytes in vitro in the absence of microglia, likely by promoting inflammatory signals in the astrocytes. FluoZin-3 live-cell imaging confirmed that neuroinflammation also induces the release of intracellular zinc from metallothionein-3 (MT3) and contributes to a positive feedback loop. Neuroinflammation-mediated A1 astrocytosis was partially attenuated when intracellular zinc is depleted by co-treatment with 1μM tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a potent zinc chelator, or genetic knockout of MT3. Collectively, our findings show that zinc plays a crucial role in the induction of A1 astrocytes by interacting with the classic neuroinflammatory pathway in a bidirectional manner.