The role of NLRP3-CASP1 in inflammasome-mediated neuroinflammation and autophagy dysfunction in manganese-induced, hippocampal-dependent impairment of learning and memory ability
The role of NLRP3-CASP1 in inflammasome-mediated neuroinflammation and autophagy dysfunction in manganese-induced, hippocampal-dependent impairment of learning and memory ability
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NLRP3-CASP1 在炎症小体介导的神经炎症和自噬功能障碍中的作用，在锰诱导的海马依赖性学习和记忆能力损伤中的作用
DOI：
10.1080/15548627.2017.1293766
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发表时间：
2017-01-01
期刊：
影响因子：
13.3
通讯作者：
Luo, Wenjing
中科院分区：
文献类型：
--
作者：
Wang, Diya;Zhang, Jianbin;Luo, Wenjing
中枢神经系统（CNS）炎症和自噬功能障碍已知与神经退行性疾病的病理过程有关。锰（Mn）是一种神经毒性金属，有可能诱导小胶质细胞介导的神经炎症以及自噬功能障碍。小胶质细胞中NLRP3（NLR家族，含热蛋白结构域3） - CASP1（半胱天冬酶1）炎症小体介导的神经炎症与神经系统疾病具有特定的相关性。然而，驱动这些现象的机制仍知之甚少。我们证明锰通过触发自噬 - 溶酶体功能障碍激活小鼠海马体和BV2细胞中的NLRP3 - CASP1炎症小体途径。自噬 - 溶酶体功能障碍是由过量锰积累导致的溶酶体损伤引起的，这种损伤破坏了这些细胞器的结构和正常功能。此外，我们表明溶酶体CTSB（组织蛋白酶B）的释放对锰诱导的NLRP3 - CASP1炎症小体激活起重要作用，并且细胞质中自噬体的增加不是NLRP3 - CASP1炎症小体激活的主要原因。促炎细胞因子如IL1B（白细胞介素1β）和IL18（白细胞介素18）的积累以及自噬途径功能障碍可能损害海马神经元细胞，从而导致海马依赖性学习和记忆障碍，这与阿尔茨海默病（AD）的发病机制有关。
ABSTRACT Central nervous system (CNS) inflammation and autophagy dysfunction are known to be involved in the pathology of neurodegenerative diseases. Manganese (Mn), a neurotoxic metal, has the potential to induce microglia-mediated neuroinflammation as well as autophagy dysfunction. NLRP3 (NLR family, pyrin domain containing 3)- CASP1 (caspase 1) inflammasome-mediated neuroinflammation in microglia has specific relevance to neurological diseases. However, the mechanism driving these phenomena remains poorly understood. We demonstrate that Mn activates the NLRP3-CASP1 inflammasome pathway in the hippocampus of mice and BV2 cells by triggering autophagy-lysosomal dysfunction. The autophagy-lysosomal dysfunction is induced by lysosomal damage caused by excessive Mn accumulation, damaging the structure and normal function of these organelles. Additionally, we show that the release of lysosomal CTSB (cathepsin B) plays an important role in Mn-induced NLRP3-CASP1 inflammasome activation, and that the increased autophagosomes in the cytoplasm are not the main cause of NLRP3-CASP1 inflammasome activation. The accumulation of proinflammatory cytokines, such as IL1B (interleukin 1 β) and IL18 (interleukin 18), as well as the dysfunctional autophagy pathway may damage hippocampal neuronal cells, thus leading to hippocampal-dependent impairment in learning and memory, which is associated with the pathogenesis of Alzheimer disease (AD).