Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
Department of Medicine Huddinge, Karolinska Institutet, 141 52 Huddinge, Sweden.
ACS Nano. 2023 Sep 12;17(17):17451-17467. doi: 10.1021/acsnano.3c05600. Epub 2023 Aug 29.
Nanoparticles (NPs) elicit sterile inflammation, but the underlying signaling pathways are poorly understood. Here, we report that human monocytes are particularly vulnerable to amorphous silica NPs, as evidenced by single-cell-based analysis of peripheral blood mononuclear cells using cytometry by time-of-flight (CyToF), while silane modification of the NPs mitigated their toxicity. Using human THP-1 cells as a model, we observed cellular internalization of silica NPs by nanoscale secondary ion mass spectrometry (nanoSIMS) and this was confirmed by transmission electron microscopy. Lipid droplet accumulation was also noted in the exposed cells. Furthermore, time-of-flight secondary ion mass spectrometry (ToF-SIMS) revealed specific changes in plasma membrane lipids, including phosphatidylcholine (PC) in silica NP-exposed cells, and subsequent studies suggested that lysophosphatidylcholine (LPC) acts as a cell autonomous signal for inflammasome activation in the absence of priming with a microbial ligand. Moreover, we found that silica NPs elicited NLRP3 inflammasome activation in monocytes, whereas cell death transpired through a non-apoptotic, lipid peroxidation-dependent mechanism. Together, these data further our understanding of the mechanism of sterile inflammation.
纳米颗粒（NPs）会引发无菌性炎症，但其中的信号通路仍知之甚少。在这里，我们报告称，单核细胞特别容易受到无定形二氧化硅 NPs 的影响，这可以通过使用飞行时间（CyToF）的单细胞分析外周血单核细胞来证明，而 NPs 的硅烷修饰减轻了它们的毒性。使用人 THP-1 细胞作为模型，我们通过纳米二次离子质谱（nanoSIMS）观察到二氧化硅 NPs 的细胞内摄取，这通过透射电子显微镜得到了证实。暴露的细胞中也注意到了脂质滴的积累。此外，飞行时间二次离子质谱（ToF-SIMS）显示了质膜脂质的特定变化，包括暴露于二氧化硅 NP 的细胞中的磷脂酰胆碱（PC），随后的研究表明，溶血磷脂酰胆碱（LPC）在没有微生物配体引发的情况下作为细胞自主信号，用于炎症小体的激活。此外，我们发现二氧化硅 NPs 会引发单核细胞中的 NLRP3 炎症小体激活，而细胞死亡则通过非凋亡、脂质过氧化依赖性机制发生。总之，这些数据进一步加深了我们对无菌性炎症机制的理解。
