Emerging research has highlighted the capacity of microRNA-23a-3p (miR-23a-3p) to alleviate inflammatory pain. However, the molecular mechanism by which miR-23a-3p attenuates inflammatory pain is yet to be fully understood. Hence, the current study aimed to elucidate the mechanism by which miR-23a-3p influences inflammatory pain. Bioinformatics was initially performed to predict the inflammatory pain related downstream targets of miR-23a-3p in macrophage-derived extracellular vesicles (EVs). An animal inflammatory pain model was established using Complete Freund's Adjuvant (CFA). The miR-23a-3p expression was downregulated in the microglia of CFA-induced mice, after which the inflammatory factors were determined by ELISA. FISH and immunofluorescence were performed to analyze the co-localization of miR-23a-3p and microglia. Interestingly, miR-23a-3p was transported to the microglia via M2 macrophage-EVs, which elevated the mechanical allodynia and the thermal hyperalgesia thresholds in mice model. The miR-23a-3p downstream target, USP5, was found to stabilize HDAC2 via deubiquitination to promote its expression while inhibiting the expression of NRF2. Taken together, the key findings of the current study demonstrate that macrophage-derived EVs containing miR-23a-3p regulates the HDAC2/NRF2 axis by decreasing USP5 expression to alleviate inflammatory pain, which may provide novel therapeutic targets for the treatment of inflammatory pain.

中文翻译：

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巨噬细胞衍生的细胞外囊泡调节 USP5 介导的 HDAC2/NRF2 轴以改善炎症性疼痛

新兴研究强调了 microRNA-23a-3p (miR-23a-3p) 减轻炎症性疼痛的能力。然而，miR-23a-3p 减轻炎症性疼痛的分子机制尚未完全了解。因此，目前的研究旨在阐明 miR-23a-3p 影响炎症性疼痛的机制。最初进行生物信息学以预测巨噬细胞衍生的细胞外囊泡 (EV) 中与炎症性疼痛相关的 miR-23a-3p 下游靶标。使用完全弗氏佐剂(CFA)建立动物炎性疼痛模型。miR-23a-3p 表达在 CFA 诱导的小鼠小胶质细胞中下调，之后通过 ELISA 测定炎症因子。进行 FISH 和免疫荧光分析 miR-23a-3p 和小胶质细胞的共定位。有趣的是，miR-23a-3p 通过 M2 巨噬细胞-EV 转运到小胶质细胞，提高了小鼠模型中的机械异常性疼痛和热痛觉过敏阈值。发现 miR-23a-3p 下游靶标 USP5 通过去泛素化稳定 HDAC2 以促进其表达，同时抑制 NRF2 的表达。综上所述，本研究的主要发现表明，含有 miR-23a-3p 的巨噬细胞衍生的 EVs 通过降低 USP5 表达来调节 HDAC2/NRF2 轴以减轻炎症性疼痛，这可能为治疗炎症性疼痛提供新的治疗靶点。发现通过去泛素化稳定 HDAC2 以促进其表达，同时抑制 NRF2 的表达。综上所述，本研究的主要发现表明，含有 miR-23a-3p 的巨噬细胞衍生的 EVs 通过降低 USP5 表达来调节 HDAC2/NRF2 轴以减轻炎症性疼痛，这可能为治疗炎症性疼痛提供新的治疗靶点。发现通过去泛素化稳定 HDAC2 以促进其表达，同时抑制 NRF2 的表达。综上所述，本研究的主要发现表明，含有 miR-23a-3p 的巨噬细胞衍生的 EVs 通过降低 USP5 表达来调节 HDAC2/NRF2 轴以减轻炎症性疼痛，这可能为治疗炎症性疼痛提供新的治疗靶点。