Microglial are major players in neuroinflammation that have recently emerged as potential therapeutic targets for neuropathic pain. Glucose metabolic programming has been linked to differential activation state and function in microglia. Tumor necrosis factor α-induced protein 8-like-2 (TNFAIP8L2) is an important component in regulating the anti-inflammatory response. However, the role of TNFAIP8L2 in microglia differential state during neuropathic pain and its interplay with glucose metabolic reprogramming in microglia has not yet been determined. Thus, we aimed to investigate the role of TNFAIP8L2 in the status of microglia in vitro and in vivo. BV2 microglial cells were treated with lipopolysaccharides plus interferon-gamma (LPS/IFNγ) or interleukin-4 (IL-4) to induce the two different phenotypes of microglia in vitro. In vivo experiments were conducted by chronic constriction injury of the sciatic nerve (CCI). We investigated whether TNFAIP8L2 regulates glucose metabolic programming in BV2 microglial cells. The data in vitro showed that TNFAIP8L2 lowers glycolysis and increases mitochondrial oxidative phosphorylation (OXPHOS) in inflammatory microglia. Blockade of glycolytic pathway abolished TNFAIP8L2-mediated differential activation of microglia. TNFAIP8L2 suppresses inflammatory microglial activation and promotes restorative microglial activation in BV2 microglial cells and in spinal cord microglia after neuropathic pain. Furthermore, TNFAIP8L2 controls differential activation of microglia and glucose metabolic reprogramming through the MAPK/mTOR/HIF-1α signaling axis. This study reveals that TNFAIP8L2 plays a critical role in neuropathic pain, providing important insights into glucose metabolic reprogramming and microglial phenotypic transition, which indicates that TNFAIP8L2 may be used as a potential drug target for the prevention of neuropathic pain.

中文翻译：

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肿瘤坏死因子 α 诱导的蛋白 8-like-2 通过 BV2 小胶质细胞的代谢重编程和对神经性疼痛的反应控制小胶质细胞表型

小胶质细胞是神经炎症的主要参与者，最近已成为神经性疼痛的潜在治疗靶点。葡萄糖代谢编程与小胶质细胞的不同激活状态和功能有关。肿瘤坏死因子α诱导蛋白8-like-2 (TNFAIP8L2)是调节抗炎反应的重要成分。然而，TNFAIP8L2 在神经性疼痛期间小胶质细胞分化状态中的作用及其与小胶质细胞葡萄糖代谢重编程的相互作用尚未确定。因此，我们的目的是研究 TNFAIP8L2 在体外和体内小胶质细胞状态中的作用。用脂多糖加干扰素-γ (LPS/IFNγ) 或白细胞介素-4 (IL-4) 处理 BV2 小胶质细胞，在体外诱导小胶质细胞的两种不同表型。通过坐骨神经慢性压迫损伤（CCI）进行体内实验。我们研究了 TNFAIP8L2 是否调节 BV2 小胶质细胞中的葡萄糖代谢程序。体外数据显示，TNFAIP8L2 降低炎症小胶质细胞中的糖酵解并增加线粒体氧化磷酸化 (OXPHOS)。糖酵解途径的阻断消除了 TNFAIP8L2 介导的小胶质细胞的差异激活。TNFAIP8L2 抑制炎症性小胶质细胞活化，并促进神经性疼痛后 BV2 小胶质细胞和脊髓小胶质细胞的恢复性小胶质细胞活化。此外，TNFAIP8L2 通过 MAPK/mTOR/HIF-1α 信号轴控制小胶质细胞的差异激活和葡萄糖代谢重编程。这项研究揭示了TNFAIP8L2在神经病理性疼痛中发挥着关键作用，为葡萄糖代谢重编程和小胶质细胞表型转变提供了重要的见解，这表明TNFAIP8L2可能作为预防神经病理性疼痛的潜在药物靶点。