NLRP3 inflammasome-dependent pyroptosis and apoptosis in hippocampus neurons mediates depressive-like behavior in diabetic mice
NLRP3 inflammasome-dependent pyroptosis and apoptosis in hippocampus neurons mediates depressive-like behavior in diabetic mice
复制标题
海马神经元NLRP3炎症小体依赖性焦亡和凋亡介导糖尿病小鼠的抑郁样行为
DOI：
10.1016/j.bbr.2020.112684
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发表时间：
2020-08-05
影响因子：
2.7
通讯作者：
Liu, Yu-Jian
中科院分区：
文献类型：
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作者：
Li, Dong-Xia;Wang, Chang-Nan;Liu, Yu-Jian
相对大量的糖尿病患者有临床抑郁症并发症的风险，导致生活质量较差，但糖尿病相关抑郁症的确切机制尚不完全清楚。高血糖诱导的氧化应激与NACHT、LRR和PYD结构域蛋白3（NLRP 3）炎性小体激活之间的联系已被报道在糖尿病发病机制中。本研究旨在阐明NLRP 3介导的凋亡/pyroptotic神经元细胞死亡对糖尿病相关抑郁症的贡献。我们发现链脲佐菌素（STZ）诱导的糖尿病小鼠的抑郁样行为与海马NLRP 3炎性小体激活有关。高血压增加了活性氧（ROS）的产生，从而导致海马神经元中的NLRP 3炎性小体激活。结果发现，STZ治疗诱导海马细胞凋亡和pyroptotic细胞死亡，证明了增加裂解的caspase 3阳性海马神经元，TUNEL阳性细胞，蛋白水平的p53，盒，彪马，和裂解的GSDMD N-末端片段，所有这些都在NLRP 3缺陷小鼠减少。使用小鼠海马神经元细胞系HT 22，我们发现，高糖诱导凋亡和pyroptotic细胞死亡在体外NLRP 3炎性小体依赖的方式。此外，NLRP 3缺陷减轻了STZ诱导的糖尿病小鼠的抑郁样行为。我们的研究结果表明，高血糖导致海马神经元细胞凋亡和pyroptosis在NLRP 3依赖的方式，这是与抑郁表型诱发STZ诱导的糖尿病。该研究确定了NLRP 3激活在高糖诱导的神经元细胞死亡中的新功能，这进一步阐明了糖尿病相关抑郁症的发病机制和新的治疗靶点。
A relatively large number of diabetic patients risk complications of clinical depression that lead to poorer quality of life, however the precise mechanisms for diabetes-associated depression are not fully understood. Links between hyperglycemia-induced oxidative stress and NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation have been reported in the pathogenesis of diabetes. The present study aimed to elucidate the contribution of NLRP3-mediated apoptotic/pyroptotic neuronal cell death to diabetes-associated depression. We found that depressive-like behavior in streptozotocin (STZ)-induced diabetic mice was associated with hippocampal NLRP3 inflammasome activation. Hyperglycemia increased reactive oxygen species (ROS) production, thus leading to NLRP3 inflammasome activation in hippocampal neurons. It was found that STZ treatment induced apoptotic and pyroptotic cell death in the hippocampus as evidenced by increases of cleaved caspase 3 positive hippocampal neurons, TUNEL-positive cells, protein levels of p53, Box, Puma, and the cleaved GSDMD N-terminal fragment, all of which were decreased in NLRP3 deficient mice. Using murine hippocampal neuronal cell line HT22, we found that high glucose induced apoptotic and pyroptotic cell death in a NLRP3 inflammasome-dependent manner in vitro. In addition, NLRP3 deficiency alleviated depressive-like behavior in STZ-induced diabetic mice. Our results suggest that hyperglycemia results in apoptosis and pyroptosis of hippocampal neuron cells in a NLRP3-dependent manner, which was associated with the depressive phenotypes evoked by STZ-induced diabetes. The study identifies a novel function of NLRP3 activation in high glucose-induced neuronal cell death, which sheds further light on the pathogenesis and new therapeutic targets of diabetes-associated depression.