Huang Chao, Sun Mayu, Yang Yang, Wang Feng, Ma Xueqi, Li Jingquan, Wang Yilong, Ding Qiurong, Ying Hao, Song Haiyun, Wu Yongning, Jiang Yiguo, Jia Xudong, Ba Qian, Wang Hui
a Key Laboratory of Food Safety Research , Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China.
b School of Public Health , Shanghai Jiao Tong University School of Medicine , Shanghai , China.
Nanotoxicology. 2017 Aug;11(6):737-750. doi: 10.1080/17435390.2017.1349202. Epub 2017 Jul 15.
Titanium dioxide nanoparticles (TiO NPs) are widely used in foods, cosmetics, and medicine. Although the inhalation toxicity of TiO NPs has been studied, the potential adverse effects of oral exposure of low-dose TiO NPs are largely unclear. Herein, with macrophage cell lines, primary cells, and mouse models, we show that TiO NPs prime macrophages into a specific activation state characterized by excessive inflammation and suppressed innate immune function. After a month of dietary exposure in mice or exposure in vitro to TiO NPs (10 and 50 nm), the expressions of pro-inflammatory genes in macrophages were increased, and the expressions of anti-inflammatory genes were decreased. In addition, for macrophages exposed to TiO NPs in vitro and in vivo, their chemotactic, phagocytic, and bactericidal activities were lower. This imbalance in the immune system could enhance the susceptibility to infections. In mice, after a month of dietary exposure to low doses of TiO NPs, an aggravated septic shock occurred in response to lipopolysaccharide challenge, leading to elevated levels of inflammatory cytokines in serum and reduced overall survival. Moreover, TLR4-deficient mice and primary macrophages, or TLR4-independent stimuli, showed less response to TiO NPs. These results demonstrate that TiO NPs induce an abnormal state of macrophages characterized by excessive inflammation and suppressed innate immune function in a TLR4-dependent manner, which may suggest a potential health risk, particularly for those with additional complications, such as bacterial infections.
二氧化钛纳米颗粒（TiO NPs）广泛应用于食品、化妆品和医药领域。尽管已经对TiO NPs的吸入毒性进行了研究，但低剂量TiO NPs经口暴露的潜在不良影响在很大程度上仍不清楚。在此，我们利用巨噬细胞系、原代细胞和小鼠模型表明，TiO NPs可将巨噬细胞诱导为一种特定的激活状态，其特征为过度炎症反应和固有免疫功能受抑制。在小鼠经一个月的饮食暴露或体外暴露于TiO NPs（10和50纳米）后，巨噬细胞中促炎基因的表达增加，抗炎基因的表达减少。此外，对于在体外和体内暴露于TiO NPs的巨噬细胞，其趋化、吞噬和杀菌活性较低。免疫系统的这种失衡会增加感染易感性。在小鼠中，经一个月的低剂量TiO NPs饮食暴露后，对脂多糖攻击的脓毒症休克反应加重，导致血清中炎症细胞因子水平升高和总体存活率降低。此外，TLR4缺陷小鼠和原代巨噬细胞，或不依赖TLR4的刺激，对TiO NPs的反应较小。这些结果表明，TiO NPs以TLR4依赖的方式诱导巨噬细胞出现以过度炎症和固有免疫功能受抑制为特征的异常状态，这可能提示存在潜在健康风险，尤其是对于那些有其他并发症（如细菌感染）的人。
