AMPK-autophagy-mediated inhibition of microRNA-30a-5p alleviates morphine tolerance via SOCS3-dependent neuroinflammation suppression.
AMPK-autophagy-mediated inhibition of microRNA-30a-5p alleviates morphine tolerance via SOCS3-dependent neuroinflammation suppression.
复制标题
AMPK 自噬介导的 microRNA-30a-5p 抑制通过 SOCS3 依赖性神经炎症抑制减轻吗啡耐受
DOI：
10.1186/s12974-022-02384-3
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发表时间：
2022-01-29
影响因子：
9.3
通讯作者：
Liu WT
中科院分区：
文献类型：
--
作者：
Wan L;Jia RM;Ji LL;Qin XM;Hu L;Hu F;Han Y;Pan YB;Jiang CY;Liu WT
吗啡耐受的发展是管理严重疼痛的临床挑战。研究表明，神经炎症是镇痛耐受性发展的关键方面。我们发现AMPK-自噬激活可以通过抑制microRNA-30 a-5 p的加工和成熟来上调细胞因子信号转导抑制因子3（SOCS 3），从而抑制神经炎症并改善吗啡耐受。CD-1小鼠用于甩尾试验以评价吗啡耐受性。利用小胶质细胞系BV-2研究AMPK自噬介导的SOCS 3转录后调控机制。通过Western印迹和实时PCR检测促炎细胞因子。通过Western blotting、real-time PCR和免疫荧光染色检测SOCS 3和miRNA加工酶的水平。基于实验验证，miRNA-30 a-5 p可以负调控SOCS 3。AMPK激活剂AICAR、白藜芦醇和二甲双胍下调miRNA-30 a-5 p。我们发现AMPK激活剂通过自噬降解DICER和AGO 2特异性抑制小胶质细胞中miRNA-30 a-5 p的加工和成熟。此外，miRNA-30 a-5 p抑制剂通过上调小鼠中的SCOS 3显著改善吗啡耐受性。它显著增加小鼠脊髓中SOCS 3的水平，随后抑制吗啡诱导的NF-κB p65磷酸化。此外，miRNA-30 a-5 p抑制剂降低了吗啡引起的小胶质细胞中IL-1β和TNF-α的水平。AMPK-自噬激活通过抑制miRNA-30 a-5 p上调SOCS 3抑制神经炎症并改善吗啡耐受性。在线版本包含补充材料，可通过10.1186/s12974-022-02384-3获得。
The development of morphine tolerance is a clinical challenge for managing severe pain. Studies have shown that neuroinflammation is a critical aspect for the development of analgesic tolerance. We found that AMPK-autophagy activation could suppress neuroinflammation and improve morphine tolerance via the upregulation of suppressor of cytokine signaling 3 (SOCS3) by inhibiting the processing and maturation of microRNA-30a-5p. CD-1 mice were utilized for the tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 was utilized to investigate the mechanism of AMPK-autophagy-mediated posttranscriptional regulation of SOCS3. Proinflammatory cytokines were measured by western blotting and real-time PCR. The levels of SOCS3 and miRNA-processing enzymes were evaluated by western blotting, real-time PCR and immunofluorescence staining. Based on experimental verification, miRNA-30a-5p could negatively regulate SOCS3. The AMPK activators AICAR, resveratrol and metformin downregulated miRNA-30a-5p. We found that AMPK activators specifically inhibited the processing and maturation of miRNA-30a-5p in microglia by degrading DICER and AGO2 via autophagy. Furthermore, a miRNA-30a-5p inhibitor significantly improved morphine tolerance via upregulation of SCOS3 in mice. It markedly increased the level of SOCS3 in the spinal cord of mice and subsequently inhibited morphine-induced phosphorylation of NF-κB p65. In addition, a miRNA-30a-5p inhibitor decreased the levels of IL-1β and TNF-α caused by morphine in microglia. AMPK-autophagy activation suppresses neuroinflammation and improves morphine tolerance via the upregulation of SOCS3 by inhibiting miRNA-30a-5p. The online version contains supplementary material available at 10.1186/s12974-022-02384-3.
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