Manganese exposure activates the cGAS–STING–IL-17 axis and is associated with Tau and α-synuclein accumulation in mice

Excessive manganese (Mn) exposure is an environmental risk factor for neurodegeneration, yet the circuitry linking Mn‑induced innate immune activation to proteinopathy remains unclear. Here, by combining in vivo manganese chloride (MnCl 2 ) exposure in mice with BV2 microglial models, we demonstrate that the cGAS–STING pathway promotes interleukin-17 (IL‑17)‑mediated neuroinflammation and neurotoxic protein accumulation. Mice administered MnCl 2 in drinking water for five weeks showed elevated levels of Tau, phosphorylated Tau (p-Tau), and α-synuclein (α-Syn), along with activation of the cGAS–STING pathway (upregulated cGAS, STING, p‑STING, p‑IRF3), increased IL‑17 A and IL‑1β levels, and an increased proportion of differentially expressed genes from transcriptomic analysis annotated to the IL-17 pathway. In BV2 microglia, MnCl 2 similarly activated cGAS–STING and upregulated IL‑17 A and IL‑1β. CRISPR‑mediated deletion of cGAS or STING abolished Mn‑induced STING–IRF3 phosphorylation, blunted IL‑17 pathway expression, and prevented the accumulation of Tau, p‑Tau, and α‑Syn. Neutralisation of IL‑17 A with a blocking antibody partially attenuated Mn‑induced Tau and α‑Syn upregulation. Molecular docking, co‑immunoprecipitation and molecular dynamics analyses suggested potential physical associations between IL‑17 A and both Tau and α‑Syn. Collectively, our findings implicate the cGAS–STING–IL-17 axis as a candidate pathway linking Mn-induced innate immune activation to neurodegeneration-related protein aggregation.