Interleukin-1β released from macrophages stimulated with indium tin oxide nanoparticles induces epithelial-mesenchymal transition in A549 cells
Interleukin-1β released from macrophages stimulated with indium tin oxide nanoparticles induces epithelial-mesenchymal transition in A549 cells
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用氧化铟锡纳米粒子刺激释放的巨噬细胞中的白介素-1β诱导 A549 细胞中的上皮-间质转化
DOI：
10.1039/d2en00031h
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Nakajima Yoshihiro
中科院分区：
文献类型：
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作者：
Tabei Yosuke;Yokota Kazumichi;Nakajima Yoshihiro
上皮-间充质转化（EMT）是上皮细胞失去极性并获得迁移性间充质特性的关键过程，最终导致组织纤维化和癌症。氧化铟锡（ITO）是最广泛制造的材料之一，具有广泛的应用，例如平板显示器、触摸板和太阳能电池板。尽管全世界都有铟相关肺病的报道，但ITO对EMT进展的影响完全未知。在目前的研究中，我们探讨了ITO纳米颗粒（NPs）是否诱导人肺泡上皮细胞（A549细胞）EMT。我们发现，虽然ITO纳米颗粒没有直接诱导A549细胞中的EMT，从THP-1衍生的巨噬细胞（dTHP-1细胞）用ITO纳米颗粒刺激获得的条件培养基（CM）诱导A549细胞中的形态学变化，高运动性和EMT进展。与ITO NP处理的dTHP-1细胞共培养后，A549细胞表现出EMT的形态学和分子特征。此外，我们通过细胞因子阵列和细胞生理生化分析的结果，确定了通过激活炎症因子样受体蛋白3（NLRP 3）炎性体产生的白细胞介素-1 β（IL-1β）是ITO NP介导的EMT诱导剂。IL-1β介导的EMT不仅发生在A549细胞，也发生在支气管上皮细胞（BEAS-2B细胞）和原代人肺泡上皮细胞（hAEC）。此外，针对IL-1受体的中和抗体可以有效抑制ITO NP处理的dTHP-1细胞中CM引起的EMT的诱导。综上所述，这些发现表明IL-1β从用ITO纳米颗粒刺激的巨噬细胞中释放，并且能够诱导A549细胞中的EMT进展，从而潜在地触发肺纤维化的发生和发展。
Epithelial–mesenchymal transition (EMT) is a crucial process by which epithelial cells lose polarity and acquire migratory mesenchymal properties, eventually leading to tissue fibrosis and cancer. Indium tin oxide (ITO) is one of the most widely manufactured materials with broad applications, such as flat panel displays, touch panels, and solar panels. Whereas cases of indium-related lung disease have been reported worldwide, the effects of ITO on the progression of EMT are completely unknown. In the current study, we explored whether ITO nanoparticles (NPs) induce EMT in human alveolar epithelial cells (A549 cells). We found that although ITO NPs did not directly induce EMT in A549 cells, a conditioned medium (CM) obtained from THP-1-derived macrophages (dTHP-1 cells) stimulated with ITO NPs induced morphological changes, high motility, and EMT progression in A549 cells. After co-culture with ITO NP-treated dTHP-1 cells, A549 cells exhibited morphological and molecular signatures of EMT. Furthermore, we identified that interleukin-1β (IL-1β) produced via the activation of nod-like receptor protein 3 (NLRP3) inflammasome is an ITO NP-mediated EMT inducer based on the results of cytokine array as well as cellular physiological and biochemical analysis. Our results also indicated that the IL-1β-mediated EMT occurs not only in A549 cells, but also in bronchial epithelial cells (BEAS-2B cells) and primary human alveolar epithelial cells (hAEC). In addition, a neutralizing antibody against IL-1 receptor can effectively inhibit the induction of EMT caused by CM from ITO NP-treated dTHP-1 cells. Taken together, these findings suggest that IL-1β is released from macrophages stimulated with ITO NPs and is able to induce EMT progression in A549 cells, thereby potentially triggering the genesis and development of pulmonary fibrosis.