Amino-Functionalized Polystyrene Nanoparticles Activate the NLRP3 Inflammasome in Human Macrophages
Amino-Functionalized Polystyrene Nanoparticles Activate the NLRP3 Inflammasome in Human Macrophages
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DOI：
10.1021/nn203596e
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发表时间：
2011-12-01
期刊：
影响因子：
17.1
通讯作者：
Simmet, Thomas
中科院分区：
文献类型：
--
作者：
Lunov, Oleg;Syrovets, Tatiana;Simmet, Thomas
专门设计和功能化的纳米粒子在生物医学应用中具有很大的前景。然而，纳米颗粒的适用性是由其表面功能化预先决定的。在这里，我们证明了直径类似于100 nm的氨基官能化聚苯乙烯纳米颗粒（PS-NH 2），但不是羧基或非官能化颗粒，触发NIRP 3炎性小体激活和随后释放促炎性白细胞介素1 β（IL-1 β）的人巨噬细胞。PS-NH 2诱导溶酶体中时间依赖性质子积聚，与溶酶体不稳定、组织蛋白酶B释放和线粒体损伤相关！膜的线粒体活性氧簇的积累伴随着硫氧还蛋白的氧化，硫氧还蛋白是一种在维持细胞氧化还原平衡中发挥核心作用的蛋白质。氧化后，硫氧还蛋白从硫氧还蛋白相互作用蛋白（TXNIP）上解离。释放的TXNIP，反过来，与NLRP 3蛋白相互作用，导致NLRP 3蛋白的pyrin结构域的构象变化，如通过分子模拟预测的。因此，这促进了NLRP 3炎性体复合物的组装以及半胱天冬酶-1的募集和活化，通过切割pro-IL-1 β诱导IL-1 β释放。NLRP 3炎性体对于细胞因子产生的中心作用通过NLRP 3和衔接蛋白ASC的体外敲低来证实，从而证实其他炎性体不被PS-NH 2激活。PS-NH 2介导的促炎性巨噬细胞活化可被自由基清除剂N-乙酰-L-半胱氨酸拮抗，从而防止线粒体损伤、caspase-1活化和随后的IL-1 β释放。我们的研究揭示了氨基功能化纳米颗粒激活NLRP 3炎性小体的分子机制，并提出了如何拮抗这种不良反应的策略。
Specifically designed and functionalized nanoparticles hold great promise for biomedical applications. Yet, the applicability of nanoparticles is critically predetermined by their surface functionalization. Here we demonstrate that amino-functionalized polystyrene nanoparticles (PS-NH2) of similar to 100 nm in diameter, but not carboxyl- or nonfunctionalized particles, trigger NIRP3 inflammasome activation and subsequent release of proinflammatory Interleukin 1 beta (IL-1 beta) by human macrophages. PS-NH2 induced time-dependent proton accumulation in lysosomes associated with lysosomal destabilization, release of cathepsin B, and damage of the mitochondria! membrane. Accumulation of mitochondrial reactive oxygen species was accompanied by oxidation of thioredoxin, a protein playing a central role in maintaining the cellular redox balance. Upon oxidation, thioredoxin dissociated from the thioredoxin-Interacting protein (TXNIP). Liberated TXNIP, In turn, interacted with the NLRP3 protein, resulting in a conformational change of the pyrin domain of the NLRP3 protein, as was predicted by molecular modeling. Consequently, this prompted assembly of the NLRP3 inflammasome complex with recruitment and activation of caspase-1, Inducing IL-1 beta release by cleavage of pro-IL-1 beta. The central role of the NLRP3 inflammasome for cytokine production was confirmed by in vitro knockdown of NLRP3 and of the adaptor protein ASC, confirming that other Inflammasomes were not activated by PS-NH2. The PS-NH2-mediated proinflammatory macrophage activation could be antagonized by the radical scavenger N-acetyl-L-cysteine, which prevented mitochondrial damage, caspase-1 activation, and the subsequent release of IL-1 beta. Our study reveals the molecular mechanism of NLRP3 inflammasome activation by amino-functionalized nanoparticles and suggests a strategy as to how such adverse effects could be antagonized.