Melatonin ameliorates manganese-induced neurological deficits in mice by inhibiting TXNIP signaling-mediated neuroinflammation and microglial pyroptosis: Role of SIRT6.

Abstract

Manganese (Mn) overexposure induces neurocognitive deficits associated with hippocampal neuronal injury and neuroinflammation, but the cellular mechanisms underlying Mn-induced hippocampal damage remain incompletely understood. Microglial pyroptosis may amplify neuroinflammation and contribute to secondary neuronal injury; however, its involvement in Mn neurotoxicity and modulation by melatonin (Mel) remain unclear. This study investigated the protective role of Mel against Mn-induced neurological deficits using C57BL/6 mice in vivo and SIM-A9 microglial cells in vitro. Mn exposure impaired learning and memory and promoted hippocampal neuronal injury, accompanied by increased NOD-like receptor family pyrin domain-containing 3 (NLRP3)-mediated pyroptotic signaling in hippocampal microglia. Mel attenuated microglial pyroptosis and neuronal injury without substantially reducing Mn levels in the hippocampus, blood, or urine. Mn disrupted the thioredoxin (Trx)/thioredoxin-interacting protein (TXNIP) redox axis and enhanced TXNIP-NLRP3 interaction. Txnip overexpression strengthened this interaction and weakened the protective effect of Mel on microglial pyroptosis. Furthermore, Mel enhanced Sirtuin 6 (SIRT6) activity and nuclear SIRT6 expression, reduced H3K9ac and H3K56ac enrichment at the Txnip promoter, and suppressed Mn-induced TXNIP overexpression. These findings suggest that Mel mitigates Mn-associated hippocampal neuroinflammatory injury by partially restoring SIRT6-mediated epigenetic repression of Txnip and reducing TXNIP/NLRP3-driven microglial pyroptosis.