Copper induces microglia-mediated neuroinflammation through ROS/NF-κB pathway and mitophagy disorder.

The epidemiological correlation between copper exposure and higher risk of Parkinson disease (PD) has been recognized for a long time, and microglia-mediated neuroinflammation has reported to be an important component of the pathogenesis of PD. The present study aimed to investigate the role of microglial activation and neuroinflammation in copper neurotoxicity and the underlying mechanism of copper-induced activation of microglia. Based on the inflammatory changes in mouse brain tissues, the activation of microglia, the loss of dopaminergic neurons and the aggregation of α-syn were found in the substantia nigra. In this study we found that copper significantly caused inflammatory activation of BV2 cells. Importantly, copper increased the level of reactive oxygen species (ROS) in BV2 cells, and then activated the NF-κB pathway which acted as an early survival signal. Further study indicated that sustained copper accumulation in BV2 cells led to the decrease of mitochondrial membrane potential, reduction of Parkin and PINK1 expression, increase of P62 expression and LC3BⅡ/I ratio, as well as upregulation of NLRP3/caspase1/GSDMD axis proteins. In addition, the increased release of inflammatory factors was rescued by redox agent, NF-κB pathway inhibitor and mitophagy inducer. This work illustrated that copper exposure activates microglia to secrete inflammatory products, resulting in the pyroptosis of dopaminergic neurons, which was related to the early activation of ROS/NF-κB pathway and subsequent mitophagy disorder in BV2 cells.