Targeting mGluR1-Mediated Microglial ER Stress Mitigates Copper-Induced TBI Neuroinflammation.

Traumatic brain injury (TBI) is continuously accompanied by metal ion imbalance and neuroinflammation. Copper accumulation has been reported to exacerbate secondary brain injury, yet the mechanisms by which copper overload regulates microglial activation remain unclear. Metabotropic glutamate receptor 1 (mGluR1) has been implicated in neuroinflammatory signaling, but its role in copper-mediated TBI pathology has not been fully elucidated. LPS-stimulated BV-2 microglial cells and a controlled cortical impact (CCI) mouse model were adopted to elucidate the role of mGluR1 in copper overload-aggravated TBI. Cell viability, proliferation, apoptosis, microglial polarization, and endoplasmic reticulum stress (ERS) were evaluated using CCK-8, EdU, TUNEL staining, immunofluorescence, qRT-PCR, and Western blot analyses. In vivo, neuronal injury, microglial activation, ERS, and neurological function were assessed by histological staining, molecular assays, and behavioral tests. mGluR1 was silenced using lentiviral shRNA, and ER stress inhibition was verified using 4-phenylbutyric acid (4-PBA). Copper exposure enhanced BV-2 microglial viability and proliferation while suppressing apoptosis under inflammatory conditions. Copper also promoted microglial M1 polarization and activated ER stress signaling through increased CHOP, p-EIF2α, p-PERK, as well as p-IRE1α expression. Silencing mGluR1 significantly reversed these effects, reducing M1 polarization and ER stress activation. In vivo, copper overload aggravated neuronal injury, microglial activation, and neurological deficits in TBI mice. mGluR1 knockdown or pharmacological inhibition of ER stress markedly alleviated neuronal apoptosis, restored microglial polarization balance, reduced ER stress markers, and improved neurological outcomes. Copper overload exacerbates secondary brain injury after TBI and is associated with mGluR1-related neuroinflammatory responses, including microglial M1 polarization and ER stress activation. Targeting the mGluR1-ER stress axis could constitute a promising therapeutic intervention for mitigating neuroinflammation and improving recovery following TBI.