State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, 200237, China.
Shanghai Collaborative Innovation Center for Biomanufacturing Technology (SCICBT), Shanghai, 200237, China.
Mol Neurobiol. 2023 Feb;60(2):596-609. doi: 10.1007/s12035-022-03098-6. Epub 2022 Nov 3.
Acrylamide (ACR), a soft electrophile, is a typical environmental and food contaminant that presents potential health hazards and, consequently, is attracting increasing attention in the quest for its control. ACR neurotoxicity has been widely reported in experimental animals and attributed to neuroinflammation; however, the mechanisms involved therein require clarification. In this study, we used a neuron cell model to investigate the mechanisms of ACR-induced neuroinflammation and pyroptosis. The results showed that ACR treatment induced lytic cell death morphologically under both the canonical pyroptotic pathway (NOD-like receptor protein 3 (NLRP3)-apoptosis-associated speck-like protein containing CARD (ASC)-cysteinyl aspartate specific proteinase 1 (caspase-1)-gasdermin D (GSDMD)-interleukin-1β (IL-1β)/interleukin-18 (IL-18)) and an alternative pyroptotic pathway (cysteinyl aspartate specific proteinase 3 (caspase-3)-gasdermin E (GSDME)-IL-1β/IL-18) in SH-SY5Y cells. Moreover, the lactate dehydrogenase (LDH) production, cytokines release, and lytic cell death induced by ACR were diminished by caspase-1 and -3 inhibitors. Furthermore, the knockdown of caspase-1 by small interfering RNA attenuated ACR-induced lytic cell death, suggesting that canonical pyroptosis (the NLRP3-caspase 1-GSDMD-IL-1β signaling axis) played a primary role in the ACR-induced pyroptosis. Of the two pyroptotic-related pathways, the NLRP3 inflammasome cascade was activated first within the 6-h period of ACR exposure, while the activation of the alternative pyroptotic pathway was delayed. Collectively, these results indicate that ACR mainly induces NLRP3-related neuroinflammation and pyroptosis in SH-SY5Y cells, which is, thus, suggestive of an alternative mechanism for ACR-induced neurotoxicity.
丙烯酰胺（ACR）是一种软的亲电试剂，是一种典型的环境和食品污染物，具有潜在的健康危害，因此在控制丙烯酰胺方面受到越来越多的关注。丙烯酰胺的神经毒性已在实验动物中广泛报道，并归因于神经炎症；然而，其中涉及的机制仍需阐明。在本研究中，我们使用神经元细胞模型来研究 ACR 诱导的神经炎症和细胞焦亡的机制。结果表明，ACR 处理在经典的细胞焦亡途径（NOD 样受体蛋白 3（NLRP3）-凋亡相关斑点样蛋白含有 CARD（ASC）-半胱氨酸天冬氨酸特异性蛋白酶 1（caspase-1）-gasdermin D（GSDMD）-白细胞介素-1β（IL-1β）/白细胞介素-18（IL-18））和替代细胞焦亡途径（半胱氨酸天冬氨酸特异性蛋白酶 3（caspase-3）-gasdermin E（GSDME）-IL-1β/IL-18）下诱导 SH-SY5Y 细胞裂解性细胞死亡。此外，caspase-1 和 caspase-3 抑制剂可减少 ACR 诱导的乳酸脱氢酶（LDH）释放、细胞因子释放和裂解性细胞死亡。此外，小干扰 RNA 敲低 caspase-1 可减弱 ACR 诱导的裂解性细胞死亡，表明经典细胞焦亡（NLRP3-caspase-1-GSDMD-IL-1β 信号轴）在 ACR 诱导的细胞焦亡中起主要作用。在两种与细胞焦亡相关的途径中，NLRP3 炎性小体级联在 ACR 暴露的 6 小时内首先被激活，而替代细胞焦亡途径的激活被延迟。总之，这些结果表明 ACR 主要在 SH-SY5Y 细胞中诱导 NLRP3 相关的神经炎症和细胞焦亡，这提示了 ACR 诱导神经毒性的另一种机制。
