Size-Dependent Attenuation of TLR9 Signaling by Gold Nanoparticles in Macrophages
Size-Dependent Attenuation of TLR9 Signaling by Gold Nanoparticles in Macrophages
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DOI：
10.4049/jimmunol.1100344
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发表时间：
2012-01-01
影响因子：
4.4
通讯作者：
Lei, Huan-Yao
中科院分区：
文献类型：
--
作者：
Tsai, Chiau-Yuang;Lu, Shiou-Ling;Lei, Huan-Yao
金纳米粒子（GNP），通常被认为是生物惰性和无细胞毒性的，已成为最理想的纳米材料之一，用于医疗应用。一旦被吞噬细胞吞噬，GNP的免疫效应仍然令人担忧，需要详细的研究。因此，本研究探讨了GNP对TLR介导的小鼠巨噬细胞天然免疫的免疫学意义。GNP引起巨噬细胞中TLR 9（CpG寡脱氧核苷酸; CpG-ODN）信号的特异性抑制。在鼠Raw 264.7细胞中，CpG-ODN诱导的TNF-α产生受损是GNP浓度和大小依赖性的：大小为4 nm的GNP比大小为11、19、35或45 nm的GNP更有效。与细胞因子抑制一致，CpG-ODN诱导的NF-κ B和JNK的磷酸化以及NF-κ B活化被GNP抑制。GNP在吞噬后在溶酶体中积累，并且还增加TLR 9相关的溶酶体组织蛋白酶表达和活性，但这与我们的研究中GNP对TLR 9的抑制无关。此外，GNP影响TLR 9易位响应CpG-ODN和吞噬体。进一步探索GNP如何抑制TLR 9功能，我们发现GNP可以结合溶酶体内的高迁移率族蛋白盒-1（其参与调节TLR 9信号传导）。目前的研究表明，GNP对TLR 9功能的大小依赖性抑制可能归因于其与高迁移率族蛋白-1的结合。免疫学杂志，2012，188：68-76。
Gold nanoparticles (GNPs), which are generally thought to be bio-inert and non-cytotoxic, have become one of the most ideal nanomaterials for medical applications. Once engulfed by phagocytes, the immunological effects of GNPs are still of concern and require detailed investigation. Therefore, this study explored the immunological significance of GNPs on TLR-mediated innate immunity in murine macrophages. GNP causes specific inhibition of TLR9 (CpG oligodeoxynucleotides; CpG-ODNs) signal in macrophages. The impaired CpG-ODN-induced TNF-alpha production is GNP concentration-and size-dependent in murine Raw264.7 cells: a GNP of 4 nm in size is more potent than a GNP of 11, 19, 35, or 45 nm in size. Consistent with cytokine inhibition, the CpG-ODN-induced phosphorylation of NF-kappa B and JNK as well as NF-kappa B activation are suppressed by GNPs. GNPs accumulate in lysosomes after phagocytosis and also increase TLR9-associated lysosomal cathepsin expression and activities, but this is irrelevant to TLR9 inhibition by GNPs in our studies. In addition, GNPs affected TLR9 translocation in response to CpG-ODNs and to phagosomes. Further exploring how GNPs inhibited TLR9 function, we found that GNPs could bind to high-mobility group box-1 (which is involved in the regulation of TLR9 signaling) inside the lysosomes. The current studies demonstrate that size-dependent inhibition of TLR9 function by GNP may be attributed to its binding to high-mobility group box-1. The Journal of Immunology, 2012, 188: 68-76.