Morphine-mediated release of miR-138 in astrocyte-derived extracellular vesicles promotes microglial activation.
Morphine-mediated release of miR-138 in astrocyte-derived extracellular vesicles promotes microglial activation.
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吗啡介导的miR-138在星形胶质细胞衍生的细胞外囊泡中的释放促进了小胶质细胞活化。
DOI：
10.1002/jev2.12027
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发表时间：
2020-10
影响因子：
16
通讯作者：
Buch S
中科院分区：
文献类型：
--
作者：
Liao K;Niu F;Hu G;Yang L;Dallon B;Villarreal D;Buch S
阿片类药物，如吗啡，是治疗术后疼痛的主要药物。在过去十年中，与阿片类药物过量有关的死亡人数急剧增加。虽然阿片类药物滥用已被证明会导致神经炎症增加，但这一过程背后的机制仍不太清楚。近年来，microRNA已成为调节旁分泌信号和细胞串扰的基因表达的关键介质。miRNA构成细胞外囊泡（EV）货物，并且可以从供体穿梭到受体细胞。将人原代星形胶质细胞暴露于吗啡导致从培养的星形胶质细胞的条件培养基中分离的EV中miR-138的诱导和释放。释放的EV反过来又被小胶质细胞吸收，导致后者细胞的激活。有趣的是，小胶质细胞的活化涉及miR 138的GUUGUGU基序与内体toll样受体（TLR）7的结合，进而导致细胞活化。这些发现在野生型小鼠体内得到进一步证实，其中吗啡给药导致丘脑中小胶质细胞活化增加。另一方面，在TLR 7 −/−小鼠中，吗啡未能诱导小胶质细胞活化。这些发现对EV负载的抗miRNAs的开发具有重要意义，可作为缓解阿片类药物滥用者神经炎症的治疗药物。
Opioids, such as morphine, are the mainstay for the management of postsurgical pain. Over the last decade there has been a dramatic increase in deaths related to opioid overdose. While opioid abuse has been shown to result in increased neuroinflammation, mechanism(s) underlying this process, remain less understood. In recent years, microRNAs have emerged as key mediators of gene expression regulating both paracrine signaling and cellular crosstalk. MiRNAs constitute the extracellular vesicle (EV) cargo and can shuttle from the donor to the recipient cells. Exposure of human primary astrocytes to morphine resulted in induction and release of miR‐138 in the EVs isolated from conditioned media of cultured astrocytes. Released EVs were, in turn, taken up by the microglia, leading to activation of these latter cells. Interestingly, activation of microglia involved binding of the GUUGUGU motif of miR138 to the endosomal toll like receptor (TLR)7, leading, in turn, to cellular activation. These findings were further corroborated in vivo in wildtype mice wherein morphine administration resulted in increased microglial activation in the thalamus. In TLR7−/− mice on the other hand, morphine failed to induce microglial activation. These findings have ramifications for the development of EV‐loaded anti‐miRNAs as therapeutics for alleviating neuroinflammation in opioids abusers.
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影响因子：
5.3
作者：
Fernández-Arjona MDM;Grondona JM;Granados-Durán P;Fernández-Llebrez P;López-Ávalos MD
通讯作者：
López-Ávalos MD
影响因子：
3.4
作者：
Bowyer, John F.;Sarkar, Sumit;Hanig, Joseph P.
通讯作者：
Hanig, Joseph P.
DOI：
10.1073/pnas.1209414109
发表时间：
2012-07-31
影响因子：
11.1
作者：
Fabbri, Muller;Paone, Alessio;Croce, Carlo M.
通讯作者：
Croce, Carlo M.
DOI：
10.1083/jcb.201605065
发表时间：
2016-10-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cai Y;Yang L;Hu G;Chen X;Niu F;Yuan L;Liu H;Xiong H;Arikkath J;Buch S
通讯作者：
Buch S
影响因子：
--
作者：
Casamayor M;DiDonato K;Hennebert M;Brazzi L;Prosen G
通讯作者：
Prosen G