NLRP3 gene knockout blocks NF-κB and MAPK signaling pathway in CUMS-induced depression mouse model

作者：Su, Wen-Jun; Zhang, Yi; Chen, Ying; Gong, Hong; Lian, Yong-Jie; Peng, Wei; Liu, Yun-Zi; Wang, Yun-Xia; You, Zi-Li; Feng, Shi-Jie; Zong, Ying; Lu, Guo-Cai^*; Jiang, Chun-Lei^*

来源：Behavioural Brain Research, 2017, 322(Pt A): 1-8.

DOI：10.1016/j.bbr.2017.01.018

• NLRP3 inflammasome
• Knockout
• Interleukin-1 beta
• Depression
• Stress
• Inflammation

Background: Abundant researches indicate that neuroinflammation has important roles in the pathophysiology of depression. Our previous study found that the NLRP3 inflammasome mediated stress-induced depression-like behavior in mice via regulating neuroinflammation. However, it still remains unclear that how the NLRP3 inflammasome influences related inflammatory signaling pathway to contribute to neuroinflammation in depression. @@@ Methods: We used wild-type mice and NLRP3 gene knockout mice to explore the role of NLRP3 inflammasome and related inflammatory signaling pathways in chronic unpredictable mild stress (CUMS) induced depression mouse model. @@@ Results: Both wild-type and NLRP3 knockout stress group mice gained less weight than control group mice after 4 weeks CUMS exposure. The wild-type mice subjected to 4 weeks CUMS displayed depression-like behaviors, including decreased sucrose preference and increased immobility time in the tail suspension test. The NLRP3 knockout stress group mice didn't demonstrate depression-like behaviors. The levels of interleukin-1 beta protein in serum and hippocampi of CUMS exposed wild-type mice were significantly higher, while the NLRP3 knockout stress group mice didn't show an elevation of interleukin-1 beta levels. Similarly to early researches, we found that CUMS led to promoted NLRP3 expression in hippocampi. In addition, the hippocampi in CUMS exposed wild-type mice had higher p-JNK and p-p38 protein expression, which indicated activation of the mitogen-activated protein kinases (MAPK) pathway. The knockout of NLRP3 gene inhibited CUMS-induced activation of the MAPK pathway. The nuclear factor kappa-light chain -enhancer of activated B cells (NF-kappa B) protein complex was activated in the hippocampi of wild-type mice after CUMS exposure, while knockout of NLRP3 gene hindered its activation. @@@ Conclusions: These data further proved that the NLRP3 inflammasome mediated CUMS-induced depression-like behavior. The NLRP3 inflammasome regulated CUMS-induced MAPK pathway and NF-kappa B protein complex activation in depression mouse model. Further researches targeting the NLRP3 inflammasome-signaling pathway might be under a promising future in the prevention and treatment of depression.

• 出版日期2017-3-30
• 单位电子科技大学; 中国人民解放军第八一医院; 中国人民解放军第二军医大学