Chronic morphine-induced microRNA-124 promotes microglial immunosuppression by modulating P65 and TRAF6.
Chronic morphine-induced microRNA-124 promotes microglial immunosuppression by modulating P65 and TRAF6.
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慢性吗啡诱导的 microRNA-124 通过调节 P65 和 TRAF6 促进小胶质细胞免疫抑制。
DOI：
10.4049/jimmunol.1400106
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发表时间：
2015-02-01
期刊：
影响因子：
--
通讯作者：
Yin D
中科院分区：
文献类型：
--
作者：
Qiu S;Feng Y;LeSage G;Zhang Y;Stuart C;He L;Li Y;Caudle Y;Peng Y;Yin D
几个世纪以来，阿片类药物作为最有效的止痛药之一广泛应用于临床，但其滥用具有有害的生理效应，包括免疫抑制。然而，其机制尚不清楚。Toll样受体（TLR）和乙酰胆碱（ACh）在免疫和神经系统中广泛表达，并在免疫应答中起关键作用。在这里，我们表明，吗啡抑制小胶质细胞和骨髓源性巨噬细胞（BMM）的先天免疫，通过不同的调节TLR和乙酰胆碱酯酶（AChE）。吗啡或ACh抑制均显著促进小胶质细胞、BMM和小鼠脑中microRNA-124（miR-124）的上调，其中miR-124通过直接靶向NF-κB p65亚基和TNF受体相关因子6（TRAF 6）介导吗啡对先天免疫的抑制。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，急性吗啡处理瞬时上调了细胞核和细胞质中p65和磷酸化p65的表达，引发了miR-124的表达，而长期暴露于吗啡维持了miR-124的表达，抑制了p65和TRAF 6依赖的TLR信号传导。这些数据表明，miR的调节能够防止阿片类药物诱导的小胶质细胞损伤。
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. Toll-like receptors (TLRs) and acetylcholine (ACh) are widely expressed in the immune and nervous systems and play critical roles in immune responses. Here we show that morphine suppresses the innate immunity in microglia and bone marrow-derived macrophages (BMM) through differential regulation of TLRs and acetylcholinesterase (AChE). Either morphine or inhibition of ACh significantly promoted up-regulation of microRNA-124 (miR-124) in microglia, BMM, and in the mouse brain, where miR-124 mediates morphine inhibition of the innate immunity by directly targeting a subunit of NF-κB p65 and TNF receptor-associated factor 6 (TRAF6). Furthermore, transcription factors AP-1 and CREB inhibited miR-124, while p65 bound directly to promoters of miR-124, thereby enhancing miR-124 transcription. Moreover, acute morphine treatment transiently up-regulated 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.
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影响因子：
15.1
作者：
Campbell, Lee A.;Avdoshina, Valeriya;Rozzi, Summer;Mocchetti, Italo
通讯作者：
Mocchetti, Italo
DOI：
10.1523/jneurosci.2419-10.2010
发表时间：
2010-07-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
He Y;Yang C;Kirkmire CM;Wang ZJ
通讯作者：
Wang ZJ
影响因子：
15.1
作者：
Hutchinson, Mark R.;Zhang, Yingning;Shridhar, Mitesh;Evans, John H.;Buchanan, Madison M.;Zhao, Tina X.;Slivka, Peter F.;Coats, Benjamen D.;Rezvani, Niloofar;Wieseler, Julie;Hughes, Travis S.;Landgraf, Kyle E.;Chan, Stefanie;Fong, Stephanie;Phipps, Simon;Falke, Joseph J.;Leinwand, Leslie A.;Maier, Steven F.;Yin, Hang;Rice, Kenner C.;Watkins, Linda R.
通讯作者：
Watkins, Linda R.
影响因子：
3.6
作者：
Boerner, Christine;Hoellt, Volker;Kraus, Juergen
通讯作者：
Kraus, Juergen
影响因子：
64.8
作者：
Bohn, LM;Gainetdinov, RR;Caron, MG
通讯作者：
Caron, MG