Loss of sTREM2 exacerbates silver nanoparticle-induced ferroptosis driven by microglia-mediated neuroinflammation: In vivo and in vitro evidence.

Silver nanoparticles (AgNPs) have been extensively applied in biomedicine fields owing to their potent antibacterial properties. Nevertheless, their propensity to accumulate in the brain has aroused substantial neurotoxicological concerns. Currently, the mechanisms underlying AgNP-induced neurotoxicity remain incompletely elucidated. In response to this research gap, the present study centers on AgNP-triggered ferroptosis and examines whether microglial polarization drives this pathology. It further explores how sTREM2 may regulate the interplay among AgNP exposure, neuroinflammation, and ferroptosis. Using C57BL/6 mice and HMC3 microglial cells as in vivo and in vitro models, a multidisciplinary approach incorporating neurobehavioral assessment, histopathological analysis, and molecular biology techniques was employed. Results showed that AgNPs reduced exploratory behavior in mice and induced neuronal morphological and ultrastructural damage. In both models, AgNPs triggered Fe2+ overload, elevated lipid peroxidation, glutathione depletion, and aberrant expression of ferroptosis-related proteins, suggesting a link to ferroptosis. Mechanistically, AgNPs appeared to downregulate sTREM2, facilitating NF-κB activation and pro-inflammatory cytokine release from microglia, thereby triggering a neuroinflammation-oxidative stress-ferroptosis cascade. Exogenous sTREM2 supplementation, the NF-κB inhibitor PDTC, or the COX-2 inhibitor celecoxib each alleviated neuroinflammation, restored redox balance, and reversed ferroptosis. Collectively, these findings provide in vivo and in vitro correlational evidence that that sTREM2 deficiency is associated with aggravated AgNPs-induced ferroptosis through microglia-driven neuroinflammatory activation. This study provides reliable experimental evidence for establishing an adverse outcome pathway (AOP) framework for AgNP-induced neurotoxicity and for developing related immunomodulatory intervention strategies.