Melatonin Ameliorate neuroinflammation in activated microglia through the Aryl hydrocarbon-Nrf2 axis

Microglia-mediated neuroinflammation is central to many neurological disorders. The Aryl hydrocarbon receptor (AhR) is highly expressed in microglia and plays a key role in neuroinflammation. While melatonin has anti-inflammatory effects in neurodegenerative disorders, its connection to AhR in modulating neuroinflammation is unclear. This study found that melatonin inhibits NF-κB activity, reduces pro-inflammatory mediators, and promotes an M2 microglia profile. Melatonin also enhances phospho-AhR (Tyr239) activation, increases Nrf2 expression, and decreases LPS-induced ROS generation in microglia. Melatonin's effects are similar to those achieved by AhR activation. In contrast, AhR knockout worsens neurological deficits and microglial activation, while melatonin reverses these effects by restoring AhR expression. In conclusion, effects of melatonin on microglia-mediated neuroinflammation are closely linked to phospho-AhR (Tyr239) activation and its associated downstream gene, Nrf2, via the AhR/Nrf2/ARE pathway. Therefore, melatonin, in conjunction with AhR may offer promising therapeutic benefits in neuroinflammatory disorders.