NIMA-related kinase 7 amplifies NLRP3 inflammasome pro-inflammatory signaling in microglia/macrophages and mice models of spinal cord injury
Xubiao Ji 1 , Zhiwen Song 2 , Junsheng He 2 , Shiwu Guo 2 , Yuwei Chen 2 , Honghai Wang 2 , Jinlong Zhang 2 , Xu Xu 2 , Jinbo Liu 3
- 1 Department of Spinal Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China; Department of Orthopedics, The Affiliated Wujin Hospital of Jiangsu University, Changzhou, 213003, China.
- 2 Department of Spinal Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.
- 3 Department of Spinal Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China. Electronic address: email@example.com.
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.
Keywords: Inflammasome; Microglia/Macrophage; NEK7; NLRP3; Spinal cord injury.