Kinaret Pia Anneli Sofia, Scala Giovanni, Federico Antonio, Sund Jukka, Greco Dario
Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, 00790, Finland.
Faculty of Biological Sciences, University of Naples, Naples, 80100, Italy.
Small. 2020 May;16(21):e1907609. doi: 10.1002/smll.201907609. Epub 2020 Apr 6.
Toxic effects of certain carbon nanomaterials (CNM) have been observed in several exposure scenarios both in vivo and in vitro. However, most of the data currently available has been generated in a high-dose/acute exposure setup, limiting the understanding of their immunomodulatory mechanisms. Here, macrophage-like THP-1 cells, exposed to ten different CNM for 48 h in low-cytotoxic concentration of 10 µg mL , are characterized by secretion of different cytokines and global transcriptional changes. Subsequently, the relationships between cytokine secretion and transcriptional patterns are modeled, highlighting specific pathways related to alternative macrophage activation. Finally, time- and dose-dependent activation of transcription and secretion of M1 marker genes IL-1β and tumor necrosis factor, and M2 marker genes IL-10 and CSF1 is confirmed among the three most responsive CNM, with concentrations of 5, 10, and 20 µg mL at 24, 48, and 72 h of exposure. These results underline CNM effects on the formation of cell microenvironment and gene expression leading to specific patterns of macrophage polarization. Taken together, these findings imply that, instead of a high and toxic CNM dose, a sub-lethal dose in controlled exposure setup can be utilized to alter the cell microenvironment and program antigen presenting cells, with fascinating implications for novel therapeutic strategies.
在体内和体外的多种暴露情况下，均已观察到某些碳纳米材料（CNM）的毒性作用。然而，目前可得的大多数数据是在高剂量/急性暴露条件下生成的，这限制了对其免疫调节机制的理解。在此，巨噬细胞样THP-1细胞在10 µg/mL的低细胞毒性浓度下暴露于十种不同的碳纳米材料48小时，通过不同细胞因子的分泌和整体转录变化来表征。随后，对细胞因子分泌与转录模式之间的关系进行建模，突出与替代性巨噬细胞激活相关的特定途径。最后，在三种反应最强烈的碳纳米材料中，证实了M1标记基因IL-1β和肿瘤坏死因子以及M2标记基因IL-10和CSF1在24、48和72小时暴露时，在5、10和20 µg/mL浓度下转录和分泌的时间和剂量依赖性激活。这些结果强调了碳纳米材料对细胞微环境形成和基因表达的影响，导致巨噬细胞极化的特定模式。综上所述，这些发现表明，与高毒性的碳纳米材料剂量不同，在可控暴露条件下的亚致死剂量可用于改变细胞微环境并对抗原呈递细胞进行编程，这对新型治疗策略具有引人入胜的意义。
