Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson's disease.
Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson's disease.
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抑制 NLRP3 炎性体激活可预防威尔逊病小鼠模型中铜诱导的神经病理学
DOI：
10.1038/s41419-021-03397-1
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发表时间：
2021-01-18
影响因子：
9
通讯作者：
Han Y
中科院分区：
文献类型：
--
作者：
Dong J;Wang X;Xu C;Gao M;Wang S;Zhang J;Tong H;Wang L;Han Y;Cheng N;Han Y
威尔逊氏病（WD）是一种遗传性疾病，其特征是体内铜的过度积累，特别是在肝脏和大脑。在中枢神经系统（CNS）中，细胞外铜积累触发病理性小胶质细胞激活和随后的神经毒性。越来越多的证据表明，小鼠WD模型的大脑中炎症细胞因子水平升高。然而，铜沉积与神经炎症的相关机制尚未完全阐明。在这项研究中，我们研究了NLR家族pyrin结构域3 （NLRP3）炎性体的激活如何在WD动物模型中参与铜介导的神经炎症。WD患者和毒乳小鼠血清中白细胞介素-1β、白细胞介素-18、白细胞介素-6和肿瘤坏死因子-α水平升高。含有c -末端caspase募集域（ASC）的炎性小体接头分子凋亡相关斑点样蛋白、cleaved caspase-1和白细胞介素-1β的蛋白水平在TX小鼠脑区上调。NLRP3炎性体在TX小鼠大脑中被激活。此外，在CuCl2处理的原发性小胶质细胞中，NLRP3炎性体被激活，并伴有裂解caspase-1、ASC和白细胞介素-1β水平的升高。用siNlrp3或MCC950阻断NLRP3炎性体激活，可减少白细胞介素-1β和白细胞介素-18的产生，从而有效减轻TX小鼠的认知能力下降、运动行为障碍和神经退行性变。总之，我们的研究证明了铜超载介导的NLRP3炎性体激活对小鼠WD模型中枢神经系统进行性神经病理的贡献。因此，阻断NLRP3炎性体激活可能是WD的一种潜在治疗策略。
Wilson’s disease (WD) is an inherited disorder characterized by excessive accumulation of copper in the body, particularly in the liver and brain. In the central nervous system (CNS), extracellular copper accumulation triggers pathological microglial activation and subsequent neurotoxicity. Growing evidence suggests that levels of inflammatory cytokines are elevated in the brain of murine WD models. However, the mechanisms associated with copper deposition to neuroinflammation have not been completely elucidated. In this study, we investigated how the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome contributes to copper-mediated neuroinflammation in an animal model of WD. Elevated levels of interleukin-1β, interleukin-18, interleukin-6, and tumor necrosis factor-α were observed in the sera of WD patients and toxic milk (TX) mice. The protein levels of inflammasome adaptor molecule apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), cleaved caspase-1, and interleukin-1β were upregulated in the brain regions of the TX mice. The NLRP3 inflammasome was activated in the TX mice brains. Furthermore, the activation of NLRP3 inflammasome was noted in primary microglia treated with CuCl2, accompanied by the increased levels of cleaved caspase-1, ASC, and interleukin-1β. Blocking NLRP3 inflammasome activation with siNlrp3 or MCC950 reduced interleukin-1β and interleukin-18 production, thereby effectively mitigating cognitive decline, locomotor behavior impairment, and neurodegeneration in TX mice. Overall, our study demonstrates the contribution of copper overload-mediated activation of NLRP3 inflammasome to progressive neuropathology in the CNS of a murine model of WD. Therefore, blockade of the NLRP3 inflammasome activation could be a potential therapeutic strategy for WD.
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