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 μg/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.

中文翻译：

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NIMA相关激酶7在小胶质细胞/巨噬细胞和脊髓损伤小鼠模型中放大NLRP3炎性体促炎信号

背景

NIMA相关激酶7（NEK7）是一种丝氨酸/苏氨酸激酶，可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态。它也是NOD样受体3（NLRP3）炎性小体促炎作用的关键调节剂。但是，NEK7在脊髓损伤后小胶质细胞/巨噬细胞中的作用尚不清楚。

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，脊髓内施用NEK7 siRNA。为了进行体外分析，用1μg/ ml脂多糖（LPS）和2 mM三磷酸腺苷（ATP）刺激带有NEK7-siRNA的BV-2小胶质细胞。

结果

在这里，我们发现受损小鼠和暴露于脂多糖（LPS）和三磷酸腺苷（ATP）的BV-2小胶质细胞的脊髓组织中NEK7和NLRP3炎性小体的mRNA和蛋白水平上调。进一步的实验表明，NEK7和NLRP3在BV-2小胶质细胞中相互作用，这种作用在消融NEK7后被消除。此外，NEK7消融抑制了NLRP3炎性小体的激活。尽管NEK7抑制并没有显着改善小鼠SCI后的运动功能，但发现它可以减弱受损脊髓的小胶质细胞/巨噬细胞中的局部炎症反应并抑制NLRP3炎性小体的活化。

结论

NEK7放大BV-2小胶质细胞和SCI小鼠模型中的NLRP3炎性体促炎信号。因此，靶向NEK7 / NLRP3信号传导的药物为治疗SCI后的炎症反应提供了广阔的前景。