Wang Yuran, Wang Zeming, Hao Han, Zhao Yuwei, Wang Jian, Wang Weixuan
School of Public Health, North China University of Science and Technology, Tangshan 063210, China.
Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, Tangshan 063210, China.
Toxics. 2025 Jan 5;13(1):37. doi: 10.3390/toxics13010037.
Hypertension is not merely a vascular disorder but a significant risk factor for neural impairment. Moreover, healthcare for the hypertensive population with environmental or occupational pollutants has become an issue of increasing concern in public health. As a traditional neurotoxic heavy metal, Pb exposure results in neuroinflammation as well as neurodegenerative diseases. The current study aimed to investigate the mechanisms of neuroinflammation in hypertensive mice exposed to Pb. We demonstrated that hypertension exacerbated Pb-induced neuroinflammation in the prefrontal cortex (PFC), hippocampus, and hypothalamus, as evidenced by increased levels of proinflammatory cytokines (IL-6 and TNF-α) and decreased levels of anti-inflammatory cytokines (CD206 and IL-10). Additionally, hypertension enhanced the neuroinflammatory response in microglia, as indicated by similar changes in cytokine expression in an in vitro cell model. Importantly, we found that TREM2, a key regulator of microglial inflammation, was downregulated in hypertensive mice with Pb exposure. This decline in TREM2 expression was associated with increased proteolysis of TREM2 by a disintegrin and metalloproteases 10 (ADAM10) as well as a disintegrin and metalloproteases 17 (ADAM17), in which ADAM17 was verified as the main cleavage enzyme in terms of TREM2 proteolytic cleavage in hypertensive mice following Pb exposure. Furthermore, we identified miR-26a-5p as a potential regulator of ADAM17 expression, suggesting a potential mechanism for the downregulation of TREM2 in this context. Our findings provided new insights into the complex interplay between hypertension, Pb exposure, and neuroinflammation as well as highlight the potential role of TREM2, ADAM17, and miR-26a-5p as therapeutic targets for neuroinflammation in hypertensive populations with Pb exposure.
高血压不仅是一种血管疾病，还是神经损伤的重要危险因素。此外，对暴露于环境或职业污染物中的高血压人群的医疗保健已成为公共卫生领域日益关注的问题。作为一种传统的神经毒性重金属，铅暴露会导致神经炎症以及神经退行性疾病。当前的研究旨在探究铅暴露的高血压小鼠神经炎症的机制。我们证明，高血压加剧了铅诱导的前额叶皮质（PFC）、海马体和下丘脑的神经炎症，促炎细胞因子（IL-6和TNF-α）水平升高以及抗炎细胞因子（CD206和IL-10）水平降低证明了这一点。此外，高血压增强了小胶质细胞中的神经炎症反应，体外细胞模型中细胞因子表达的类似变化表明了这一点。重要的是，我们发现小胶质细胞炎症的关键调节因子TREM2在铅暴露的高血压小鼠中下调。TREM2表达的这种下降与金属蛋白酶10（ADAM10）和金属蛋白酶17（ADAM17）对TREM2的蛋白水解增加有关，其中ADAM17被证实是铅暴露后高血压小鼠中TREM2蛋白水解切割的主要切割酶。此外，我们确定miR-26a-5p是ADAM17表达的潜在调节因子，这表明在这种情况下TREM2下调的潜在机制。我们的研究结果为高血压、铅暴露和神经炎症之间的复杂相互作用提供了新的见解，并突出了TREM2、ADAM17和miR-26a-5p作为铅暴露高血压人群神经炎症治疗靶点的潜在作用。
