Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson's disease

doi:10.1038/s41419-021-03397-1

HFCAS OpenIR

	Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson's disease
	Dong, Jianjian 1,2,3; Wang, Xun 3,4; Xu, Chenchen 3,4; Gao, Manli 3,4; Wang, Shijing 3,4; Zhang, Jin1 ; Tong, Haiyang1 ; Wang, Lulu1 ; Han, Yongzhu 3,4; Cheng, Nan 3,4; Han, Yongsheng 3,4
	2021-01-18
发表期刊	CELL DEATH & DISEASE
ISSN	2041-4889
通讯作者	Cheng, Nan(NanCheng111065@ahtcm.edu.cn) ; Han, Yongsheng(hyysp@ahtcm.edu.cn)
摘要	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-1 beta, interleukin-18, interleukin-6, and tumor necrosis factor-alpha 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-1 beta 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-1 beta. Blocking NLRP3 inflammasome activation with siNlrp3 or MCC950 reduced interleukin-1 beta 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.
DOI	10.1038/s41419-021-03397-1
关键词[WOS]	NF-KAPPA-B ; MECHANISMS ; MICROGLIA
收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China[81603596] ; National Natural Science Foundation of China[81673948] ; National Natural Science Foundation of China[81904086] ; National Natural Science Foundation of China[81774425] ; Natural Science Foundation of Anhui University of Chinese Medicine[2020sjzd03] ; Natural Science Foundation of Anhui Province[1808085MH245]
项目资助者	National Natural Science Foundation of China ; Natural Science Foundation of Anhui University of Chinese Medicine ; Natural Science Foundation of Anhui Province
WOS研究方向	Cell Biology
WOS类目	Cell Biology
WOS记录号	WOS:000611916800001
出版者	SPRINGERNATURE
引用统计	被引频次：45[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://ir.hfcas.ac.cn:8080/handle/334002/119675
专题	中国科学院合肥物质科学研究院
通讯作者	Cheng, Nan; Han, Yongsheng
作者单位	1.Chinese Acad Sci, Hefei Inst Phys Sci, High Magnet Field Lab, Hefei 230031, Peoples R China 2.Univ Sci & Technol China, Hefei 230026, Peoples R China 3.Anhui Univ Chinese Med, Neurol Inst, Affiliated Hosp, Hefei 230061, Peoples R China 4.Anhui Univ Chinese Med, Hefei 230012, Peoples R China
推荐引用方式 GB/T 7714	Dong, Jianjian,Wang, Xun,Xu, Chenchen,et al. Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson's disease[J]. CELL DEATH & DISEASE,2021,12.
APA	Dong, Jianjian.,Wang, Xun.,Xu, Chenchen.,Gao, Manli.,Wang, Shijing.,...&Han, Yongsheng.(2021).Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson's disease.CELL DEATH & DISEASE,12.
MLA	Dong, Jianjian,et al."Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson's disease".CELL DEATH & DISEASE 12(2021).