Paraquat induced neuro-immunotoxicity: Dysregulated microglial antigen processing and mitochondrial activated mechanisms

Paraquat (PQ) is characterized by neurotoxicity. In daily life, PQ exposure mainly occurs through chronic and trace pathways, which induce progressive neuronal damage or neuronal synaptic loss. Previously, mitochondrial dysfunction was a critical underlying mechanism. Emerging evidence suggests that neuroinflammation mediated by microglial activation and T-cell infiltration may trigger accelerated neuronal degeneration. While antigen presentation constitutes an essential prerequisite for T-cell infiltration and functional activation, the potential association between mitochondrial impairment and microglial antigen presentation dysregulation remains unexplored. In this study, we initially identified paraquat-associated target gene clusters from the CTD database. Following the enrichment analyses of GO and KEGG revealed Parkinson's disease pathways and mitochondrial processes. Further, we constructed a time-dependent model for C57BL/6J (♂) mice continuously treated with PQ (1.25 mg/kg) once/day to imitate early-stage neurotoxicity. For mice, neurobehavioral symptoms showed a decrease in learning and memory abilities. Pathologically, the neuroinflammatory response dominated by microglial activation and T-cell infiltration preceded observable synaptic loss. This correlated with microglial two distinct processes: 1) upregulated surface chemokine expression (CCL2, CCL3, CCL4, CCL5), and 2) enhanced antigen recognition, phagocytosis, and presentation machinery (TLR4, LAMP2, MHC II), facilitating CD4⁺/CD8⁺ T-cell recruitment. Notably, α-synuclein aggregates may act as antigens triggering microglial mitochondrial stress responses, as evidenced by altered expression of mitochondrial proteases (LONP1, ClpP, HTRA2). Remarkably, resveratrol effectively restored BV-2 microglial mitochondrial homeostasis and normalized antigen presentation. This study demonstrated that microglial mitochondrial dysregulation mediates aberrant antigen presentation, thereby driving neuroinflammatory cascades. And provides novel and potential mechanistic insights into chemical neurotoxicity.

Antigen presentation; Microglia; Mitochondrion; Paraquat; T-cell infiltration.