Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
Environ Pollut. 2021 Oct 15;287:117520. doi: 10.1016/j.envpol.2021.117520. Epub 2021 Jun 15.
Neuroinflammation induced by lead exposure (Pb) is a major cause of neurotoxicity of Pb in the central nervous system (CNS). The NLR family, domain of pyrin containing 3 (NLRP3) involves in various neurological diseases, while the question of whether NLRP3 plays a role in lead-induced neuroinflammation has not yet been reported.
Developmental and knockout (KO) NLRP3 mice were used to establish two in vivo models, and BV2 cells were used to establish an in vitro model. Behavioral and electrophysiologic tests were used to assess the neurotoxicity of Pb, and immunofluorescence staining was used to assess neuroinflammation. Real-time PCR and western blot were performed to examine the mRNA and protein levels of inflammatory cytokines and NLRP3 inflammasomes. siRNA technology was used to block NLRP3 expression.
Pb exposure led to neural injure and microglial activation in the hippocampus region, while minocycline intervention attenuated Pb-induced neurotoxicity by inhibiting neuroinflammation. Pb increased the expression of NLRP3 and promoted cleavage of caspase-1 in mRNA and protein levels, and minocycline partially reversed the effects of Pb on NLRP3 inflammasomes. Blocking of NLRP3 by KO mice or siRNA attenuated neural alterations induced by Pb, weakened microglial activation in vivo and in vitro as well, without affecting the accumulation of Pb. Pb increased autophagic protein levels and phosphorylation of NF-κB, while suppressing autophagy or NF-κB inhibited Pb's effects on NLRP3.
NLRP3 is involved in the regulation of Pb-induced neurotoxicity. These findings expand mechanism research of Pb neurotoxicity and may help establish new prevention strategies for Pb neurotoxicity.
铅暴露引起的神经炎症是铅在中枢神经系统（CNS）中产生神经毒性的主要原因。含pyrin 结构域的 N 端样受体家族 3（NLRP3）参与多种神经疾病，然而，NLRP3 是否在铅诱导的神经炎症中发挥作用尚未见报道。
采用发育型和敲除（KO）NLRP3 小鼠建立两种体内模型，并采用 BV2 细胞建立体外模型。采用行为学和电生理学测试评估铅的神经毒性，采用免疫荧光染色评估神经炎症。实时 PCR 和 Western blot 检测炎症细胞因子和 NLRP3 炎性小体的 mRNA 和蛋白水平。采用 siRNA 技术阻断 NLRP3 表达。
铅暴露导致海马区神经损伤和小胶质细胞激活，米诺环素干预通过抑制神经炎症减轻铅诱导的神经毒性。铅增加 NLRP3 的表达，并促进 caspase-1 在 mRNA 和蛋白水平的裂解，米诺环素部分逆转了铅对 NLRP3 炎性小体的作用。KO 小鼠或 siRNA 阻断 NLRP3 减弱了铅诱导的神经改变，减弱了体内和体外小胶质细胞的激活，而不影响铅的积累。铅增加自噬蛋白水平和 NF-κB 的磷酸化，而抑制自噬或 NF-κB 抑制了铅对 NLRP3 的作用。
NLRP3 参与了铅诱导的神经毒性的调节。这些发现扩展了铅神经毒性的机制研究，并可能有助于建立铅神经毒性的新预防策略。
