Human umbilical cord mesenchymal stem cell-derived extracellular vesicles alleviated silica induced lung inflammation and fibrosis in mice via circPWWP2A/miR-223-3p/NLRP3 axis
Human umbilical cord mesenchymal stem cell-derived extracellular vesicles alleviated silica induced lung inflammation and fibrosis in mice via circPWWP2A/miR-223-3p/NLRP3 axis
复制标题
人脐带间充质干细胞来源的细胞外囊泡通过 circPWWP2A/miR-223-3p/NLRP3 轴减轻二氧化硅诱导的小鼠肺部炎症和纤维化
DOI：
10.1016/j.ecoenv.2023.114537
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发表时间：
2023-01-14
影响因子：
6.8
通讯作者：
Tian, Lin
中科院分区：
文献类型：
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作者：
Hou, Lin;Zhu, Zhonghui;Tian, Lin
矽肺是一种进行性炎症性疾病，发病机制不明确，治疗选择有限。最近的研究发现，microRNAs(MiRNAs)和CircRNAs(CircRNAs)参与了呼吸系统疾病的发生发展，但非编码RNAs在矽肺中的作用仍有待进一步研究。我们发现，二氧化硅处理后，小鼠巨噬细胞和肺组织中miR-223-3p的表达显著减少，这与GEO数据库芯片分析的结果一致。值得注意的是，NLRP3是miR-223-3p下游的一个靶基因。二氧化硅刺激后，环状RNA PWWP2A(CircPWWP2A)显著升高。为了阐明这些RNA在二氧化硅诱导的巨噬细胞和肺组织炎症中的作用，我们研究了CircPWWP2A在炎症反应中的上游分子机制。通过抑制miR-223-3p对靶基因NLRP3的抑制作用，导致肺纤维化。我们的研究发现，在肺纤维化的二氧化硅刺激后，CircPWWP2A可以吸附miR-223-3p来调节NLRP3。我们的结果表明，CircPWWP2A-miR-223-3p-NLRP3轴在控制二氧化硅诱导的炎症和纤维化中具有潜在的作用。以往的研究表明，人脐带间充质干细胞来源的细胞外小泡(hucMSC-EVS)在多个器官具有抗炎和抗纤维化的作用。然而，hucMSC-EVS对矽肺的潜在疗效或其生物学结果的潜在机制仍不清楚。因此，我们采用三维培养技术提取hucMSC-EVS，并分别观察其在巨噬细胞和肺组织中的作用。根据EVmiRNA数据库，miR-223-3p在MSC-EVS中含量丰富。此外，hucMSC-EVS还可以调节肺功能，减少炎症因子(NLRP3、IL-1β、IL-18和裂解的Caspase-1)的分泌，并减少纤维化相关因子(胶原I、胶原III、纤维连接蛋白和α-SMA)的沉积。体外实验结果表明，hucMSC-Evs可降低巨噬细胞的炎症反应，抑制成纤维细胞的活化和增殖。此外，我们的研究还表明，hucMSCs-EVS作为一种媒介，通过转导miR-223-3p来抑制CircPWWP2A，从而通过NLRP3信号通路减轻肺纤维化。这些数据可能为研究矽肺的发病机制和开发新的治疗方法提供潜在的新策略。
Silicosis is a progressive inflammatory disease with poorly defined mechanisms and limited therapeutic options. Recent studies found that microRNAs (miRNAs) and circular RNAs (circRNAs) were involved in the development of respiratory diseases; however, the function of non-coding RNAs in silicosis was still needed to be further explored. We found that miR-223-3p was significantly decreased in macrophages and lung tissues of mice after silica treatment, which were consistent with the results of GEO database microarray analysis. Notably, NLRP3 is a target gene downstream of miR-223-3p. And circular RNA PWWP2A (circPWWP2A) was significantly elevated after silica stimulation. To elucidate the role of these RNAs in silica-induced inflammation in macrophages and lung tissues, we investigated the upstream molecular mechanisms of circPWWP2A on the inflammatory response. The inhibitory effect of miR-223-3p on its target NLRP3 was suppressed by circPWWP2A, which led to lung fibrosis. Our study found that circPWWP2A could adsorb miR-223-3p to regulate NLRP3 after silica stimulation in pulmonary fibrosis. And our results revealed that the circPWWP2A-miR-223-3p-NLRP3 axis was potentially instrumental in managing silica-induced inflammation and fibrosis. Previous studies have demonstrated that human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hucMSC-EVs) exhibit anti-inflammatory and anti-fibrotic effects in multiple organs. However, the potential effectiveness of hucMSC-EVs against silicosis or the underlying mechanisms of their biological outcomes remains unclear. Therefore, we used 3D culture technology to extract hucMSC-EVs and observed their effects in macrophages and lung tissues, respectively. According to the EVmiRNA database, miR-223-3p was abundant in MSC-EVs. In addition, hucMSC-EVs may modulate lung function, reduce the secretion of inflammatory factors (NLRP3, IL-1 beta, IL-18 and cleaved Caspase-1) and attenuate the deposition of fibrosis-related factors (Collagen I, Collagen III, fibronectin and alpha-SMA). In vitro results evinced that hucMSC-EVs reduced the inflammatory response of macrophages and restricted the activation and proliferation of fibroblasts. Moreover, our study showed that hucMSCs-EVs acted as a mediator to transfer miR-223-3p to suppress circPWWP2A, thereby alleviating pulmonary fibrosis through the NLRP3 signaling pathway. These data may provide potentially novel strategies for investigating the pathogenesis of silicosis and developing novel treatments for this disease.