NIMA-related kinase 7 amplifies NLRP3 inflammasome pro-inflammatory signaling in microglia/macrophages and mice models of spinal cord injury
NIMA-related kinase 7 amplifies NLRP3 inflammasome pro-inflammatory signaling in microglia/macrophages and mice models of spinal cord injury
复制标题
NIMA 相关激酶 7 放大小胶质细胞/巨噬细胞和脊髓损伤小鼠模型中的 NLRP3 炎性体促炎信号传导
DOI：
10.1016/j.yexcr.2020.112418
复制
发表时间：
2021-01-15
影响因子：
3.7
通讯作者：
Liu, Jinbo
中科院分区：
文献类型：
--
作者：
Ji, Xubiao;Song, Zhiwen;Liu, Jinbo
工作背景：NIMA相关激酶-7（NEK7）是一种丝氨酸/苏氨酸激酶，通过调节有丝分裂纺锤体形成和胞质分裂来驱动细胞周期动力学。它也是NOD样受体3（NLRP 3）炎性小体的促炎作用的重要调节剂。然而，NEK7在脊髓损伤后小胶质细胞/巨噬细胞中的作用还没有很好的定义。方法：在这项研究中，我们进行了体内和体外实验。使用体内小鼠SCI模型，脊柱内施用NEK7 siRNA。对于体外分析，用1 μ g/ml脂多糖（LPS）和2 mM三磷酸腺苷（ATP）刺激具有NEK7-siRNA的BV-2小胶质细胞。结果：在这里，我们发现在损伤小鼠的脊髓组织和暴露于脂多糖（LPS）和三磷酸腺苷（ATP）的BV-2小胶质细胞中，NEK7和NLRP 3炎性小体的mRNA和蛋白水平上调。进一步的实验证实，NEK7和NLRP 3在BV-2小胶质细胞中相互作用，这种作用在NEK7消融后被消除。此外，NEK7消融抑制了NLRP 3炎性小体的活化。虽然NEK7抑制并没有显着改善运动功能后SCI小鼠，它被发现减弱局部炎症反应和抑制NLRP 3炎症体的激活在小胶质细胞/巨噬细胞的损伤spinalcord.Conclusion：NEK7放大NLRP 3炎症体促炎症信号在BV-2小胶质细胞和SCI小鼠模型。因此，靶向NEK7/NLRP3信号传导的药物在SCI后炎症反应的治疗中提供了很大的希望。
Background: NIMA-related kinase-7 (NEK7) is a serine/threonine kinase that drives cell-cycle dynamics by modulating mitotic spindle formation and cytokinesis. It is also a crucial modulator of the pro-inflammatory effects of NOD-like receptor 3 (NLRP3) inflammasome. However, the role of NEK7 in microglia/macrophages post-spinal cord injury (SCI) is not well defined.Methods: In this study, we performed both in vivo and in vitro experiments. Using an in vivo mouse SCI model, NEK7 siRNAs were administered intraspinally. For in vitro analysis, BV-2 microglia cells with NEK7-siRNA were stimulated with 1 mu g/ml lipopolysaccharide (LPS) and 2 mM Adenosine triphosphate (ATP).Results: Here, we found that the mRNA and protein levels of NEK7 and NLRP3 inflammasomes were upregulated in spinal cord tissues of injured mice and BV-2 microglia cells exposed to Lipopolysaccharide (LPS) and Adenosine triphosphate (ATP). Further experiments established that NEK7 and NLRP3 interacted in BV-2 microglia cells, an effect that was eliminated following NEK7 ablation. Moreover, NEK7 ablation suppressed the activation of NLRP3 inflammasomes. Although NEK7 inhibition did not significantly improve motor function post-SCI in mice, it was found to attenuate local inflammatory response and inhibit the activation of NLRP3 inflammasome in microglia/macrophages of the injured spinal cord.Conclusion: NEK7 amplifies NLRP3 inflammasome pro-inflammatory signaling in BV-2 microglia cells and mice models of SCI. Therefore, agents targeting the NEK7/NLRP3 signaling offers great promise in the treatment of inflammatory response post-SCI.