Luo Yilin, Zhang Kun, Mao Lejiao, Tan Meiling, Dong Xiaomei, Li Na, Zhou Yuexing, Chen Chengzhi, Zou Zhen, Zhang Jun
Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, PR China.
Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, PR China.
Toxicology. 2025 May;513:154101. doi: 10.1016/j.tox.2025.154101. Epub 2025 Feb 21.
Macrophage-derived foam cells are crucial in the development of atherosclerosis, a multifaceted and progressive disorder characterized by lipid and fibrous accumulation in major arteries. Copper oxide nanoparticles (CuONPs) have found widespread applications but their potential role in atherosclerosis remains understudied. In this study, we investigated the impact of CuONPs on foam cell formation in RAW264.7 macrophages. Our results showed that CuONPs, at concentrations as low as 10 μg/ml, significantly exacerbated foam cell formation induced by oxidized low-density lipoprotein (ox-LDL). Exposure to CuONPs stimulated LDL release and elevated the expression of NLRP3 inflammasome components, including NLRP3, Caspase-1, and IL-1β. Transmission electron microscopy (TEM) revealed accumulation of CuONPs within macrophage lysosomes, leading to disrupted lysosomal function. CuONPs-treated cells exhibited autophagosome accumulation due to impaired lysosomal degradation, as confirmed by Western blot analysis showing abnormal expression of LAMP-1 and LAMP-2 proteins. Flow cytometry analysis further demonstrated decreased lysosomal acidity in CuONPs-exposed cells. Our findings reveal a novel mechanism whereby CuONPs activate the inflammasome, disrupt lysosomal function, and hinder cholesterol efflux, thereby exacerbating the formation of macrophage-derived foam cells. These results highlight the potential risks of CuONPs exposure and provide important insights into the role of environmental particulate matter in the development of atherosclerosis.
巨噬细胞源性泡沫细胞在动脉粥样硬化的发展过程中起着关键作用，动脉粥样硬化是一种多方面的渐进性疾病，其特征是主要动脉中脂质和纤维的积累。氧化铜纳米颗粒（CuONPs）已得到广泛应用，但其在动脉粥样硬化中的潜在作用仍未得到充分研究。在本研究中，我们调查了CuONPs对RAW264.7巨噬细胞中泡沫细胞形成的影响。我们的结果表明，低至10μg/ml浓度的CuONPs显著加剧了氧化低密度脂蛋白（ox-LDL）诱导的泡沫细胞形成。暴露于CuONPs刺激了低密度脂蛋白（LDL）的释放，并提高了NLRP3炎性小体成分的表达，包括NLRP3、半胱天冬酶-1和白细胞介素-1β。透射电子显微镜（TEM）显示CuONPs在巨噬细胞溶酶体内积累，导致溶酶体功能破坏。Western blot分析显示LAMP-1和LAMP-2蛋白表达异常，证实CuONPs处理的细胞由于溶酶体降解受损而出现自噬体积累。流式细胞术分析进一步证明暴露于CuONPs的细胞中溶酶体酸度降低。我们的研究结果揭示了一种新机制，即CuONPs激活炎性小体、破坏溶酶体功能并阻碍胆固醇外流，从而加剧巨噬细胞源性泡沫细胞的形成。这些结果突出了暴露于CuONPs的潜在风险，并为环境颗粒物在动脉粥样硬化发展中的作用提供了重要见解。
