AQP4-knockout alleviates the lipopolysaccharide-induced inflammatory response in astrocytes via SPHK1/MAPK/AKT signaling
AQP4-knockout alleviates the lipopolysaccharide-induced inflammatory response in astrocytes via SPHK1/MAPK/AKT signaling
复制标题
AQP4™ 敲除通过 SPHK1/MAPK/AKT 信号传导减轻星形胶质细胞中脂多糖™诱导的炎症反应
DOI：
10.3892/ijmm.2018.3749
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发表时间：
2018-09-01
影响因子：
5.4
通讯作者：
Zeng, Xiaoning
中科院分区：
文献类型：
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作者：
Dai, Wangshu;Yan, Junjun;Zeng, Xiaoning
迄今为止，水通道蛋白 4 (AQP4) 被认为是神经炎症的关键因素，但对其潜在机制知之甚少。先前的研究表明，鞘磷脂循环中涉及的关键酶鞘氨醇激酶 1 (SPHK1) 与炎症过程有关，并导致慢性神经炎症。本研究调查了 AQP4 在星形胶质细胞促炎细胞因子释放中的作用，重点是 SPHK1/丝裂原激活蛋白激酶 (MAPK)/蛋白激酶 B (AKT) 通路。使用从 AQP4(+/+) 和 AQP4(-/-) 胚胎分离的原代培养物，比较脂多糖 (LPS) 攻击的星形胶质细胞产生的肿瘤坏死因子-α (TNF-α)/白细胞介素-6 (IL-6)。结果显示，LPS治疗后两组TNF-α/IL-6的分泌增加，但AQP4(/)组的水平明显低于AQP4(+/+)组。尽管在两种基因型中检测到 SPHK1 上调，但在 AQP4(-/-) 基因型中仅发现 SPHK1 轻微增加。 MAPK/AKT 的磷酸化也被证实在 AQP4 (/) 组中减弱，表明 AQP4(-/-) 星形胶质细胞中的 MAPK/AKT 信号随着时间的推移而减少。总体而言，研究结果表明，AQP4 缺陷可减轻星形胶质细胞促炎细胞因子的释放，与 SPHK1/MAPK/AKT 通路相关。这些数据提高了我们对 AQP4 在神经炎症事件中的理解，强调了 SPHK1 作为治疗中枢神经系统炎症的潜在靶点的新特征。
To date, aquaporin-4 (AQP4) has been considered as a critical contributor to neuroinflammation, but little is known about the underlying mechanism. Previous studies have shown that a critical enzyme involved in the sphingomyelin cycle, sphingosine kinase 1 (SPHK1), is implicated in inflammatory processes and contributes to chronic neuroinflammation. The present study investigated the role of AQP4 in proinflammatory cytokine release from astrocytes, with an emphasis on the SPHK1/mitogen-activated protein kinase (MAPK)/protein kinase B (AKT) pathway. Using primary cultures isolated from AQP4(+/+) and AQP4(-/-) embryos, the production of tumor necrosis factor-alpha (TNF-alpha)/interleukin-6 (IL-6) from astrocytes challenged by lipopolysaccharide (LPS) was compared. The results showed increased secretion of TNF-alpha/IL-6 in the two groups following LPS treatment, but a significantly lower level was observed in the AQP4 (/) group compared with that in the AQP4(+/+) group. Although upregulation of SPHK1 was detected in the two genotypes, only a mild increase in SPHK1 was found in the AQP4(-/-) genotype. The phosphorylation of MAPK/AKT was also confirmed to be attenuated in the AQP4 (/) group, suggesting decreased MAPK/AKT signaling over time in AQP4(-/-) astrocytes. Overall, the study findings demonstrated that AQP4 deficiency alleviates proinflammatory cytokine release from astrocytes, in association with the SPHK1/MAPK/AKTpathway. This data improves our understanding of AQP4 in neuroinflammatory events, highlighting a novel profile of SPHK1 as a potential target for the treatment of CNS inflammation.