Tumor necrosis factor primes and metal particles activate the NLRP3 inflammasome in human primary macrophages.
Tumor necrosis factor primes and metal particles activate the NLRP3 inflammasome in human primary macrophages.
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DOI：
10.1016/j.actbio.2020.03.017
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发表时间：
2020-05
影响因子：
9.7
通讯作者：
Nurmi K
中科院分区：
文献类型：
--
作者：
Jämsen E;Pajarinen J;Kouri VP;Rahikkala A;Goodman SB;Manninen M;Nordström DC;Eklund KK;Nurmi K
全关节置换物的无菌性松动是由巨噬细胞介导的对植入物产生的磨损颗粒的炎症反应驱动的。植入物碎片的吞噬作用被认为可以激活 NLRP3 炎性体，从而导致白细胞介素 (IL)-1 β 的分泌。然而，驱动颗粒诱导炎症小体激活的因素和分子机制尚未完全阐明。在这项研究中，我们在体外研究了人类原代巨噬细胞对钛、铬和钼颗粒的炎症反应。我们观察到，单独的颗粒不足以诱导 IL-1 β 分泌，但需要额外的启动信号（例如细菌脂多糖 (LPS)）来许可炎症小体激活。通过使用针对炎症小体信号通路的特异性抑制剂，我们证明颗粒诱导的 IL-1 β 分泌依赖于 NLRP3 炎症小体的激活。我们进一步假设肿瘤坏死因子 (TNF) 可以替代 LPS 作为启动信号，并发现颗粒刺激与之前的 TNF 治疗一起也会导致炎症小体依赖性 IL-1 β 的产生。我们的结果表明，NLRP3 炎症小体介导人原代巨噬细胞中的磨损颗粒反应，其激活不一定需要细菌成分的存在，但可以在无菌条件下通过 TNF 引发诱导。
Aseptic loosening of total joint replacements is driven by a macrophage-mediated inflammatory reaction to implant-derived wear particles. Phagocytosis of implant debris has been suggested to activate the NLRP3 inflammasome leading to secretion of interleukin (IL)-1 β. However, factors and molecular mechanisms driving the particle-induced inflammasome activation are yet to be fully elucidated. In this study, we investigated the inflammasome response of human primary macrophages to titanium, chromium, and molybdenum particles in vitro. We observed that particles alone were not sufficient to induce IL-1 β secretion, but an additional priming signal—such as bacterial lipopolysaccharide (LPS)—was required to license the inflammasome activation. By using specific inhibitors against the inflammasome signaling pathway, we demonstrate that the particle-induced IL-1 β secretion depended upon activation of the NLRP3 inflammasome. We further hypothesized that tumor necrosis factor (TNF) could substitute for LPS as a priming signal, and found that particle stimulation together with preceding TNF treatment resulted in inflammasome-dependent IL-1 β production as well. Our results show that the NLRP3 inflammasome mediates wear particle responses in human primary macrophages, and its activation does not necessarily require the presence of bacterial components, but can be induced under aseptic conditions by TNF priming.
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