School of Public Health and Management, Ningxia Medical University, No.1160, the Street of Shengli, Xingqing District, Yinchuan, Ningxia, China; Key Laboratory of Environmental Factors and Chronic Disease Control, No.1160, the Street of Shengli, Xingqing District, Yinchuan, Ningxia, China.
School of Public Health and Management, Ningxia Medical University, No.1160, the Street of Shengli, Xingqing District, Yinchuan, Ningxia, China; Key Laboratory of Environmental Factors and Chronic Disease Control, No.1160, the Street of Shengli, Xingqing District, Yinchuan, Ningxia, China.
Ecotoxicol Environ Saf. 2023 Mar 1;252:114583. doi: 10.1016/j.ecoenv.2023.114583. Epub 2023 Feb 1.
Atrazine (ATR) is a widely applied herbicide which was named an environmental endocrine disrupting chemical (EDC). Increasing evidence indicates ATR causes neurotoxic effects resulting in central nervous system (CNS) disease. As the primary immunocytes in the CNS, microglia cells carry out their phagocytosis to maintain the CNS microenvironment by preventing damage from healthy cells. However, the mechanism in which ATR affects the phagocytic function of microglia remains unclear. The present study was designed to investigate the effect of ATR on the phagocytosis of microglia. BV-2 cells and primary microglia selected as microglial models in which BV-2 cells were administrated by ATR at different concentrations (0, 4, 8, 16 μM) for 24 h. Results demonstrated ATR dose-dependently increased the expression of ionized calcium binding adapter molecule 1 (Iba-1), indicating that microglia were activated. Microglial phagocytotic activity induced by ATR fluctuated at the different time points, accompanied by fluctuations in membrane receptor MERTK and cytoplasmic lysosomal marker LAMP1 (two markers related to cell phagocytosis). In this period, the expression of iNOS gradually increased. A mechanistic study further demonstrated that the translocation of High Mobility Group Protein-B1 (HMGB1) from nucleus to cytoplasm in the BV-2 and primary microglial cells induced by ATR, and the process showed a positive correlation with phagocytosis activity of BV-2 cells induced by ATR (r = 0.8030, P = 0.05; α = 0.1). ATR was also shown to spur the acetylation of HMGB1 by breaking the balance between acetylase P300 and deacetylase SIRT1. Unexpectedly, the inhibition of acetylating HMGB1 by resveratrol (Res) was effectively retained by HMGB1 in the nucleus, reversed the SIRT1 and MERTK expression, and enhanced the phagocytosis activity in BV-2 cells. Our results suggested that ATR exposure influenced microglial phagocytosis by acetylating HMGB1 further translocated it in the nucleoplasm.
莠去津（ATR）是一种广泛应用的除草剂，被命名为环境内分泌干扰化学物质（EDC）。越来越多的证据表明，ATR 会导致神经毒性作用，从而导致中枢神经系统（CNS）疾病。作为中枢神经系统中的主要免疫细胞，小胶质细胞通过吞噬作用来维持中枢神经系统的微环境，防止健康细胞受到损伤。然而，ATR 影响小胶质细胞吞噬功能的机制尚不清楚。本研究旨在探讨 ATR 对小胶质细胞吞噬作用的影响。选择 BV-2 细胞和原代小胶质细胞作为小胶质细胞模型，用不同浓度（0、4、8、16μM）的 ATR 处理 BV-2 细胞 24 小时。结果表明，ATR 呈剂量依赖性地增加离子钙结合接头分子 1（Iba-1）的表达，表明小胶质细胞被激活。ATR 诱导的小胶质细胞吞噬活性在不同时间点波动，同时伴随着膜受体 MERTK 和细胞质溶酶体标记物 LAMP1（与细胞吞噬作用相关的两个标记物）的波动。在此期间，iNOS 的表达逐渐增加。进一步的机制研究表明，ATR 诱导 BV-2 和原代小胶质细胞中的高迁移率族蛋白 B1（HMGB1）从核转位到细胞质，该过程与 ATR 诱导的 BV-2 细胞吞噬活性呈正相关（r=0.8030，P=0.05；α=0.1）。ATR 还通过打破乙酰转移酶 P300 和去乙酰化酶 SIRT1 之间的平衡来刺激 HMGB1 的乙酰化。出乎意料的是，白藜芦醇（Res）通过抑制 HMGB1 的乙酰化，有效地将其保留在核内，逆转了 SIRT1 和 MERTK 的表达，并增强了 BV-2 细胞的吞噬活性。我们的结果表明，ATR 暴露通过乙酰化 HMGB1 进一步影响小胶质细胞的吞噬作用，并将其转移到核质中。
