Qiu Shuwei, Feng Yimin, LeSage Gene, Zhang Ying, Stuart Charles, He Lei, Li Yi, Caudle Yi, Peng Ying, Yin Deling
Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37614; and.
Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37614; and.
J Immunol. 2015 Feb 1;194(3):1021-30. doi: 10.4049/jimmunol.1400106. Epub 2014 Dec 24.
Opioids have been widely applied in clinics as one of the most potent pain relievers for centuries, but their abuse has deleterious physiological effects including immunosuppression. However, the mechanisms are unclear. TLRs and acetylcholine are widely expressed in the immune and nervous systems, and play critical roles in immune responses. In this article, we show that morphine suppresses the innate immunity in microglia and bone marrow-derived macrophages through differential regulation of TLRs and acetylcholinesterase. Either morphine or inhibition of acetylcholine significantly promotes upregulation of microRNA-124 (miR-124) in microglia, bone marrow-derived macrophages, and the mouse brain, where miR-124 mediates morphine inhibition of the innate immunity by directly targeting a subunit of NF-κB p65 and TNFR-associated factor 6 (TRAF6). Furthermore, transcription factors AP-1 and CREB inhibited miR-124, whereas p65 bound directly to promoters of miR-124, thereby enhancing miR-124 transcription. Moreover, acute morphine treatment transiently upregulated the expression of p65 and phospho-p65 in both nucleus and cytoplasm priming the expression of miR-124, whereas long exposure of morphine maintained miR-124 expression, which inhibited p65- and TRAF6-dependent TLR signaling. These data suggest that modulation of miRs is capable of preventing opioid-induced damage to microglia.
几个世纪以来，阿片类药物作为最有效的止痛剂之一在临床上被广泛应用，但其滥用会产生包括免疫抑制在内的有害生理影响。然而，其机制尚不清楚。Toll样受体（TLRs）和乙酰胆碱在免疫和神经系统中广泛表达，并在免疫反应中起关键作用。在本文中，我们表明吗啡通过对TLRs和乙酰胆碱酯酶的差异调节来抑制小胶质细胞和骨髓来源巨噬细胞的固有免疫。吗啡或乙酰胆碱抑制均可显著促进小胶质细胞、骨髓来源巨噬细胞和小鼠大脑中微小RNA-124（miR-124）的上调，其中miR-124通过直接靶向核因子κB p65亚基和肿瘤坏死因子受体相关因子6（TRAF6）介导吗啡对固有免疫的抑制。此外，转录因子AP-1和CREB抑制miR-124，而p65直接与miR-124的启动子结合，从而增强miR-124的转录。此外，急性吗啡处理可短暂上调细胞核和细胞质中p65和磷酸化p65的表达，引发miR-124的表达，而长期暴露于吗啡可维持miR-124的表达，从而抑制p65和TRAF6依赖性的TLR信号传导。这些数据表明，微小RNA的调节能够预防阿片类药物引起的小胶质细胞损伤。
