TREM2-mediated neuroinflammatory response is involved in AgNPs-induced ferroptosis in HMC3 cells

Silver nanoparticles (AgNPs) are widely used in industrial and biomedical applications owing to their superior physicochemical properties, especially antimicrobial activity. However, their potential health risks raise concerns. Given that the central nervous system (CNS) is a major target of AgNPs, assessing their neurotoxic effects is critical for safety evaluation. Recent studies suggest that ferroptosis may play a pivotal role in AgNPs-induced neurotoxicity, yet the underlying molecular mechanisms remain unclear. This study is the first to investigate AgNPs-triggered ferroptosis in human microglial cells (HMC3) and explore the regulatory role of triggering receptor expressed on myeloid cells 2 (TREM2)-mediated inflammatory responses. Following exposure to AgNPs (0, 50, 100, and 200 μg/mL) for 48 h, HMC3 cells exhibited dose-dependent cytotoxicity. Further analyses revealed mitochondrial ultrastructural and functional damage, intracellular Fe²⁺ overload, elevated ROS levels, GSH depletion, and increased lipid peroxidation, accompanied by dysregulated expression of ferroptosis-related proteins. Inflammatory profiling demonstrated reduced TREM2 protein levels, elevated pro-inflammatory markers, and decreased anti-inflammatory markers, indicating AgNPs-induced inflammatory responses. Treatment with the TREM2 agonist COG 1410 (5 μg/mL) significantly upregulated TREM2 expression, attenuated pro-inflammatory factors, and enhanced anti-inflammatory factors. Moreover, TREM2 activation significantly inhibited AgNPs-induced ferroptosis in HMC3 cells, indicating that TREM2-mediated inflammation may play a key role in regulating this process. These findings offer new understanding of AgNPs neurotoxicity and potential therapeutic targets for reducing CNS damage from AgNPs exposure.