Sheu Meei-Ling, Yang Cheng-Ning, Pan Liang-Yi, Sheehan Jason, Pan Liang-Yu, You Weir-Chiang, Wang Chien-Chia, Chen Ying Ju, Chen Hong-Shiu, Pan Hung-Chuan
Institute of Biomedical Science, National Chung-Hsing University, Taichung, Taiwan.
Doctoral Program in Biotechnology Industrial Management and Innovation, National Chung Hsing University, Taichung, Taiwan.
Int J Biol Sci. 2025 Jun 9;21(9):3917-3933. doi: 10.7150/ijbs.105081. eCollection 2025.
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.
小胶质细胞介导的神经炎症是许多神经疾病的核心。芳烃受体（AhR）在小胶质细胞中高度表达，并在神经炎症中起关键作用。虽然褪黑素在神经退行性疾病中具有抗炎作用，但其在调节神经炎症中与AhR的联系尚不清楚。本研究发现，褪黑素抑制NF-κB活性，减少促炎介质，并促进M2小胶质细胞表型。褪黑素还增强磷酸化AhR（Tyr239）的激活，增加Nrf2表达，并减少小胶质细胞中LPS诱导的ROS生成。褪黑素的作用与AhR激活所产生的作用相似。相反，AhR基因敲除会加重神经功能缺损和小胶质细胞激活，而褪黑素通过恢复AhR表达来逆转这些作用。总之，褪黑素对小胶质细胞介导的神经炎症的作用通过AhR/Nrf2/ARE途径与磷酸化AhR（Tyr239）激活及其相关下游基因Nrf2密切相关。因此，褪黑素与AhR联合使用可能在神经炎症性疾病中提供有前景的治疗益处。
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