Abstract

Excessive manganese (Mn) exposure is associated with neuroinflammation and cognitive impairment, yet the contribution of endogenous pro-resolving pathways to Mn neurotoxicity remains incompletely understood. Here, we examined the involvement of the lipocalin-type prostaglandin D synthase (L-PGDS)/15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) pathway using Mn-treated male C57BL/6J mice, BV2 microglia, and SH-SY5Y neurons, together with data from occupationally Mn-exposed workers (cross-sectional, hypothesis-generating). In the occupational cohort, circulating 15d-PGJ2 levels and L-PGDS expression were reduced following Mn exposure, consistent with the experimental findings. PPI network analysis and promoter prediction highlighted C/EBPβ and MMP9 as potential mediators of Mn-induced neuroinflammatory responses. Consistent with these observations, Mn exposure increased C/EBPβ and MMP9 expression, promoted M1 microglial polarization, elevated ROS production, and aggravated neuronal injury in a microglia–neuron co-culture system. Knocking down either C/EBPβ or MMP9 attenuated inflammatory activation and oxidative stress and reduced neuronal damage. Administration of exogenous 15d-PGJ2 suppressed Mn-induced increases in C/EBPβ and MMP9, alleviated inflammatory and oxidative responses, and partially ameliorated cognitive impairment in Mn-exposed mice. Transcriptomic analyses further showed that 15d-PGJ2 counteracted a substantial proportion of Mn-induced transcriptional alterations, particularly those related to inflammatory and neurodevelopmental processes. In addition, Ptgds knockdown reduced endogenous 15d-PGJ2 production and increased MMP9 expression, whereas exogenous 15d-PGJ2 largely reversed these changes. Together, these findings support the involvement of L-PGDS/15d-PGJ2 pathway dysregulation in Mn-induced neuroinflammation and suggest that restoration of 15d-PGJ2 signaling may represent a potential therapeutic approach for Mn-associated neurotoxicity.

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