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
Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, 800 Xiangyin Road, Shanghai, China.
Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, 800 Xiangyin Road, Shanghai, China; Department of Psychiatry, Faculty of Psychology and Mental Health, Second Military Medical University, 800 Xiangyin Road, Shanghai, China.
Behav Brain Res. 2017 Mar 30;322(Pt A):1-8. doi: 10.1016/j.bbr.2017.01.018. Epub 2017 Jan 16.
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.
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.
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-1β 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-1β 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-κB) protein complex was activated in the hippocampi of wild-type mice after CUMS exposure, while knockout of NLRP3 gene hindered its activation.
These data further proved that the NLRP3 inflammasome mediated CUMS-induced depression-like behavior. The NLRP3 inflammasome regulated CUMS-induced MAPK pathway and NF-κB 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.
大量研究表明，神经炎症在抑郁症的病理生理学中起着重要作用。我们之前的研究发现，NLRP3炎性小体通过调节神经炎症介导小鼠应激诱导的抑郁样行为。然而，NLRP3炎性小体如何影响相关炎症信号通路从而导致抑郁症中的神经炎症仍不清楚。
我们使用野生型小鼠和NLRP3基因敲除小鼠，以探究NLRP3炎性小体及相关炎症信号通路在慢性不可预测轻度应激（CUMS）诱导的抑郁小鼠模型中的作用。
在暴露于CUMS 4周后，野生型和NLRP3敲除应激组小鼠的体重均比对照组小鼠增加得少。接受4周CUMS的野生型小鼠表现出抑郁样行为，包括蔗糖偏好降低和悬尾试验中不动时间增加。NLRP3敲除应激组小鼠未表现出抑郁样行为。暴露于CUMS的野生型小鼠血清和海马中白细胞介素-1β蛋白水平显著更高，而NLRP3敲除应激组小鼠未显示白细胞介素-1β水平升高。与早期研究相似，我们发现CUMS导致海马中NLRP3表达升高。此外，暴露于CUMS的野生型小鼠海马中p-JNK和p-p38蛋白表达更高，这表明丝裂原活化蛋白激酶（MAPK）通路被激活。NLRP3基因敲除抑制了CUMS诱导的MAPK通路激活。暴露于CUMS后，野生型小鼠海马中的核因子κB（NF-κB）蛋白复合物被激活，而NLRP3基因敲除阻碍了其激活。
这些数据进一步证明，NLRP3炎性小体介导了CUMS诱导的抑郁样行为。在抑郁小鼠模型中，NLRP3炎性小体调节了CUMS诱导的MAPK通路和NF-κB蛋白复合物激活。针对NLRP3炎性小体信号通路的进一步研究在抑郁症的预防和治疗方面可能具有广阔前景。
