Glutamine alleviates lead-induced neuroinflammation via αKG-JMJD3-H3K27me3 pathway: Population, animal, and in vitro evidence.

Lead (Pb) exposure is linked to neuroinflammation and cognitive decline, yet the role of glutamine metabolism in this process remains unclear. In a cross-sectional study of 150 residents, we demonstrated that prolonged Pb exposure is associated with reduced Montreal Cognitive Assessment (MoCA) scores and decreased serum glutamine levels. In vivo, C57BL/6 J mice (n = 8/group) were exposed to Pb (100 mg/L in drinking water) and concurrently treated with glutamine (250 mg/kg, every other day) via gavage. Pb exposure results in learning and memory deficits, hippocampal microglial activation, and inflammatory pathological damage. Furthermore, Pb exposure disrupted hippocampal glutamine metabolism, significantly reducing glutamine, glutamate, and α-ketoglutarate (αKG) levels in a dose-dependent manner. In vitro mechanistic experiments utilizing the immortalized murine microglial cell line (BV2) (n = 3 independent replicates/group) exposed to 10 μM Pb acetate confirmed these dose-dependent metabolic disruptions. Crucially, Glutamine supplementation (250 mg/kg in vivo; 2 mM in vitro against 10 μM Pb) alleviated these impairments across both models. Pharmacological investigations suggest that the glutamine metabolite αKG enhances the expression of Jumonji domain-containing 3 (JMJD3) in microglia, which correlates with the inhibition of Pb-induced upregulation of H3K27me3 and facilitates the shift from a pro-inflammatory (M1) to an anti-inflammatory (M2) microglial phenotype. In summary, our integrated findings suggest the involvement of a novel metabolic-epigenetic axis in Pb-induced neuroinflammation and suggest glutamine metabolism as a potential target for intervention.