NLRP3 inflammasome-mediated pyroptosis involvement in cadmium exposure-induced cognitive deficits via the Sirt3-mtROS axis

Dongmei Wang; Yiran Wu; Shihao Sun; Pu Zhao; Xiang Zhou; Chen Liang; Yilu Ma; Sanqiang Li; Xiaoying Zhu; Xueqin Hao; Jian Shi; Hua Fan

doi:10.1016/j.scitotenv.2023.166478

NLRP3 inflammasome-mediated pyroptosis involvement in cadmium exposure-induced cognitive deficits via the Sirt3-mtROS axis

Sci Total Environ. 2023 Dec 10:903:166478. doi: 10.1016/j.scitotenv.2023.166478. Epub 2023 Aug 23.

Authors

Dongmei Wang¹, Yiran Wu², Shihao Sun², Pu Zhao², Xiang Zhou², Chen Liang², Yilu Ma², Sanqiang Li², Xiaoying Zhu², Xueqin Hao², Jian Shi³, Hua Fan⁴

Affiliations

¹ College of Basic Medicine and Forensic Medicine, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China. Electronic address: wdmzgadyx@163.com.
² College of Basic Medicine and Forensic Medicine, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China.
³ College of Basic Medicine and Forensic Medicine, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China. Electronic address: s_j2008@163.com.
⁴ College of Basic Medicine and Forensic Medicine, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China. Electronic address: fanhua19851229@126.com.

PMID: 37625726
DOI: 10.1016/j.scitotenv.2023.166478

Abstract

Cadmium (Cd), a toxic heavy metal, exerts deleterious effects on neuronal survival and cognitive function. NOD-like receptor 3 (NLRP3) inflammasome-dependent pyroptosis has been linked to Cd-induced cytotoxicity. The current research intended to elucidate the role of NLRP3 inflammasome-mediated pyroptosis in Cd-evoked neuronal death and cognitive impairments and the underlying mechanisms. Exposure to 1 mg/kg Cd for 8 weeks led to hippocampal-dependent cognitive deficits and neural/synaptic damage in mice. NLRP3 inflammasome-related protein expression (NLRP3, ASC, and caspase1 p20) and neuronal pyroptosis were significantly upregulated in Cd-treated hippocampi and SH-SY5Y cells. Moreover, pretreatment with the NLRP3 inhibitor MCC950 mitigated Cd-elicited NLRP3 inflammasome activation and subsequent neuronal pyroptosis in SH-SY5Y cells. Furthermore, exposure to Cd downregulated Sirt3 expression, suppressed SOD2 activity by hyperacetylation, and enhanced mtROS accumulation in vivo and in vitro. Notably, Cd-induced NLRP3 inflammasome-dependent neuronal pyroptosis was attenuated by a mtROS scavenger or Sirt3 overexpression in SH-SY5Y cells. In addition, Cd failed to further suppress SOD activity and activate NLRP3 inflammasome-dependent neuronal pyroptosis in Sirt3 shRNA-treated SH-SY5Y cells. Collectively, our findings indicate that Cd exposure induces neuronal injury and cognitive deficits by activating NLRP3 inflammasome-dependent neuronal pyroptosis and that activation of the NLRP3 inflammasome is partially mediated by the Sirt3-mtROS axis.

Keywords: Cadmium; Cognitive deficits; NLRP3 inflammasome; Pyroptosis; Sirt3-mtROS.