Spinal cord injury (SCI) is a devastating disease and causes tissue loss and neurologic dysfunction, contributing to high morbidity and disability among human. However, the underlying molecular mechanisms still remain unclear. Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a member of the TNFAIP8/TIPE family, and has been implicated in different diseases associated with inflammation, infection, and immunity. Nevertheless, its effects on SCI have not been well investigated. In our study, we found time course of TNFAIP8 following SCI in mice, along with time-dependent increases of pro-inflammatory cytokines. The in vitro results confirmed the up-regulation of TNFAIP8 induced by lipopolysaccharide (LPS). Subsequently, we found that reducing TNFAIP8 by transfection with its specific siRNA (siTNFAIP8) markedly alleviated cell viability and inflammatory response caused by LPS in mouse microglial BV2 cells. Importantly, LPS-enhanced activation of inhibitor of κBα/nuclear factor-κB (IκBα/NF-κB) and phosphoinositide 3-kinase/serine-threonine kinase (PI3K/AKT) signaling pathways was considerably blunted by siTNFAIP8. Intriguingly, our results further showed that siTNFAIP8-restrained inflammation and IκBα/NF-κB in LPS-stimulated BV2 cells were almost abolished by the pre-treatment of AKT activator SC-79, demonstrating that TNFAIP8-regulated inflammatory response was largely dependent on AKT activation. Then, the in vivo studies were performed using the wild type (WT) and TNFAIP8-knockout (KO) mice with or without SCI operation. Results showed that TNFAIP8-KO mice exhibited improved neuron injury and locomotor function along with decreased microglial activity. Furthermore, compared with the WT/SCI mice, the expression of pro-inflammatory cytokines in spinal cords was markedly down-regulated by TNFAIP8-deficiency through blocking IκBα/NF-κB and PI3K/AKT signaling pathways. Taken together, these findings elucidated the novel role of TNFAIP8 in regulating SCI via the AKT signaling, and thus TNFAIP8 may be served as a promising therapeutic target for SCI treatment.

脊髓损伤（SCI）是一种毁灭性疾病，导致组织损失和神经功能障碍，导致人类高发病率和致残性。但是，潜在的分子机制仍然不清楚。肿瘤坏死因子-α诱导蛋白8（TNFAIP8）是TNFAIP8 / TIPE家族的一员，与多种炎症，感染和免疫有关。然而，其对SCI的影响尚未得到很好的研究。在我们的研究中，我们发现了小鼠SCI后TNFAIP8的时间变化，以及促炎性细胞因子的时间依赖性增加。在体外结果证实了脂多糖（LPS）诱导的TNFAIP8的上调。随后，我们发现通过转染特定siRNA（siTNFAIP8）来降低TNFAIP8，可显着减轻小鼠小胶质BV2细胞中LPS引起的细胞活力和炎症反应。重要的是，siTNFAIP8大大抑制了LPS增强的κBα/核因子-κB（IκBα/NF-κB）和磷酸肌醇3-激酶/丝氨酸-苏氨酸激酶（PI3K / AKT）信号通路的抑制。有趣的是，我们的结果进一步表明，AKT激活剂SC-79的预处理几乎消除了LPS刺激的BV2细胞中siTNFAIP8抑制的炎症和IκBα/NF-κB，这表明TNFAIP8调节的炎症反应很大程度上取决于AKT激活。然后，体内使用野生型（WT）和TNFAIP8敲除（KO）小鼠进行或不进行SCI手术进行研究。结果显示，TNFAIP8-KO小鼠表现出改善的神经元损伤和运动功能，同时小胶质细胞活性降低。此外，与WT / SCI小鼠相比，TNFAIP8缺陷通过阻断IκBα/NF-κB和PI3K / AKT信号通路显着下调了脊髓中促炎性细胞因子的表达。综上所述，这些发现阐明了TNFAIP8在通过AKT信号传导调节SCI中的新作用，因此TNFAIP8可以作为SCI治疗的有希望的治疗靶标。