This study shows paraquat induces microglia-driven neuroinflammation that drives pro-inflammatory astrocyte polarization and dopaminergic neuron loss, effects that are reversed by microglial depletion or activation of the PI3K/AKT pathway.

By implicating PI3K/AKT-dependent microglia–astrocyte crosstalk in toxin-induced dopaminergic degeneration, the work points to a targetable inflammatory mechanism (and potential PI3K-modulating interventions) relevant to PD therapeutic development.

Paraquat (PQ), a widely used bipyridyl herbicide, exerts neurotoxic effects on dopaminergic neurons and can lead to Parkinson's disease (PD)-like syndrome. Although immune dysfunction has been implicated in PD progression, the role of neuroimmune interactions in PQ-induced neurotoxicity remains poorly understood. This study aimed to investigate the mechanism by which microglia, the innate immune cells of the central nervous system, regulate the neurotoxic effects of PQ exposure. Network toxicology analysis revealed a link between microglia-mediated neuroinflammation and PQ-induced neurodegeneration, as well as astrocyte differentiation. Single-cell RNA sequencing (scRNA-seq) analysis identified the PI3K/AKT pathway as a potential regulatory mechanism underlying astrocyte phenotypic transformation. Our experimental evidence showed that PQ exposure induced neuroinflammation, dopaminergic neuron degeneration, and a pro-inflammatory astrocytes phenotype, all of which were reversed by microglial depletion. In vitro experiments using primary astrocytes cultured in conditioned medium from PQ-activated microglia demonstrated that activated microglia promoted a pro-inflammatory astrocyte phenotype, which was associated with inhibition of the PI3K/AKT pathway. This effect was alleviated by pretreatment with a PI3K activator. Taken together, our results suggest that PQ exposure disrupts microglia-astrocytes homeostasis, leading to aberrant neuroimmune crosstalk and inflammatory cascades that may underlie dopaminergic neurodegeneration. Therefore, this work provides crucial insights into the neuroimmune mechanisms of PQ-induced pathology, thereby informing both future research and environmental health policy.