Dysregulation of macrophage activation profiles by engineered nanoparticles.
Dysregulation of macrophage activation profiles by engineered nanoparticles.
复制标题
DOI：
10.1021/nn402145t
复制
发表时间：
2013-08-27
期刊：
影响因子：
17.1
通讯作者：
Thrall BD
中科院分区：
文献类型：
--
作者：
Kodali V;Littke MH;Tilton SC;Teeguarden JG;Shi L;Frevert CW;Wang W;Pounds JG;Thrall BD
尽管接触工程纳米粒子（ENPs）对人类健康的潜在影响尚不明确，但以往的流行病学研究已经确定了接触环境空气污染颗粒物与肺炎和肺部感染发病率之间的相关性。我们以无定形二氧化硅和超顺磁性氧化铁（SPIO）作为高产量的ENPs模型，研究了细菌脂多糖（LPS）或肺部病原体肺炎链球菌对巨噬细胞的激活作用是如何被ENP预处理所改变的。二氧化硅和SPIO处理均未在骨髓来源的巨噬细胞中引发直接的细胞毒性或促炎效应。然而，用SPIO预处理巨噬细胞导致近500个受LPS刺激调控的基因发生广泛的重编程，其特征是氧化应激反应途径的过度激活以及促炎和抗炎途径激活的抑制。二氧化硅预处理仅改变了67个基因的调控，但与受SPIO影响的基因集有很强的相关性。接触SPIO的巨噬细胞表现出一种表型，表明其从M1样激活状态向M2样激活状态转变的能力受损，其特征是白细胞介素 - 10（IL - 10）诱导受到抑制、肿瘤坏死因子α（TNFα）产生增加以及对肺炎链球菌的吞噬活性降低。对清道夫受体A（SR - A）缺陷的巨噬细胞的研究表明，SR - A参与了ENPs和肺炎链球菌的细胞摄取，并共同调节抗炎性IL - 10途径。因此，由于一些ENPs和病原菌使用共同的受体识别途径，先天免疫失调的机制是存在的，尽管巨噬细胞功能的转录重编程程度取决于内化后ENP的物理化学性质。我们的研究结果还表明，ENPs的生物学效应可能只有在正常细胞功能受到挑战后才会间接显现。因此，纳米毒理学筛选策略应考虑接触这些材料如何改变对其他环境暴露的敏感性。
Although the potential human health impacts from exposure to engineered nanoparticles (ENPs) are uncertain, past epidemiological studies have established correlations between exposure to ambient air pollution particulates and the incidence of pneumonia and lung infections. Using amorphous silica and superparamagnetic iron oxide (SPIO) as model high production volume ENPs, we examined how macrophage activation by bacterial lipopolysaccharide (LPS) or the lung pathogen Streptococcus pneumoniae is altered by ENP pre-treatment. Neither silica nor SPIO treatment elicited direct cytotoxic or pro-inflammatory effects in bone marrow-derived macrophages. However, pre-treatment of macrophages with SPIO caused extensive reprogramming of nearly 500 genes regulated in response to LPS challenge, hallmarked by exaggerated activation of oxidative stress response pathways and suppressed activation of both pro- and anti-inflammatory pathways. Silica pre-treatment altered regulation of only 67 genes, but there was strong correlation with gene sets affected by SPIO. Macrophages exposed to SPIO displayed a phenotype suggesting an impaired ability to transition from a M1 to M2-like activation state, characterized by suppressed IL-10 induction, enhanced TNFα production, and diminished phagocytic activity toward S. pneumoniae. Studies in macrophages deficient in scavenger receptor A (SR-A) showed SR-A participates in cell uptake of both the ENPs and S. pneumonia, and co-regulates the anti-inflammatory IL-10 pathway. Thus, mechanisms for dysregulation of innate immunity exist by virtue that common receptor recognition pathways are used by some ENPs and pathogenic bacteria, although the extent of transcriptional reprogramming of macrophage function depends on the physicochemical properties of the ENP after internalization. Our results also illustrate that biological effects of ENPs may be indirectly manifested only after challenging normal cell function. Nanotoxicology screening strategies should therefore consider how exposure to these materials alters susceptibility to other environmental exposures.