Nie Zhihao, Fan Qinglu, Jiang Wanli, Wei Shujian, Luo Renwei, Hu Haifeng, Liu Gaoli, Lei Yufei, Xie Songping
Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
Front Immunol. 2024 Nov 15;15:1422355. doi: 10.3389/fimmu.2024.1422355. eCollection 2024.
Acute lung injury (ALI) is a clinically severe respiratory disorder that currently lacks specific and effective pharmacotherapy. The imbalance of M1/M2 macrophage polarization is pivotal in the initiation and progression of ALI. Shifting macrophage polarization from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype could be a potential therapeutic strategy. The intratracheal administration of placental mesenchymal stem cells (pMSCs) has emerged as a novel and effective treatment for ALI. This study aimed to investigate the role and downstream mechanisms of pMSCs in reprogramming macrophage polarization to exert anti-inflammatory effects in ALI.
The study used lipopolysaccharide (LPS) to induce inflammation in both cell and rat models of ALI. Intratracheal administration of pMSCs was tested as a therapeutic intervention. An expression dataset for MSCs cultured with LPS-treated macrophages was collected from the Gene Expression Omnibus database to predict downstream regulatory mechanisms. Experimental validation was conducted through in vitro and in vivo assays to assess pMSCs effects on macrophage polarization and inflammation.
Both and experiments validated that pMSCs promoted M2 macrophage polarization and reduced the release of inflammatory factors. Further analyses revealed that pMSCs activated the signal transducer and activator of transcription (STAT)3 signaling pathway by secreting interleukin (IL)-10, leading to increased STAT3 phosphorylation and nuclear translocation. This activation inhibited NLRP3 inflammasome activation, promoting M2 macrophage polarization and suppressing the inflammatory response.
The study concluded that pMSCs alleviated lung injury in an LPS-induced ALI model by inhibiting M1 macrophage polarization and proinflammatory factor secretion, while promoting M2 macrophage polarization. This effect was mediated via the IL-10/STAT3/NLRP3 axis, presenting a novel therapeutic pathway for ALI treatment.
急性肺损伤（ALI）是一种临床严重的呼吸系统疾病，目前缺乏特异性有效的药物治疗。M1/M2巨噬细胞极化失衡在ALI的发生和发展中起关键作用。将巨噬细胞极化从促炎的M1表型转变为抗炎的M2表型可能是一种潜在的治疗策略。气管内注射胎盘间充质干细胞（pMSCs）已成为治疗ALI的一种新型有效方法。本研究旨在探讨pMSCs在重编程巨噬细胞极化以发挥ALI抗炎作用中的作用及下游机制。
本研究使用脂多糖（LPS）在ALI的细胞和大鼠模型中诱导炎症。测试气管内注射pMSCs作为一种治疗干预措施。从基因表达综合数据库收集用LPS处理的巨噬细胞培养的间充质干细胞的表达数据集，以预测下游调控机制。通过体外和体内试验进行实验验证，以评估pMSCs对巨噬细胞极化和炎症的影响。
体外和体内实验均证实pMSCs促进M2巨噬细胞极化并减少炎症因子的释放。进一步分析表明，pMSCs通过分泌白细胞介素（IL）-10激活信号转导和转录激活因子（STAT）3信号通路，导致STAT3磷酸化增加和核转位。这种激活抑制了NLRP3炎性小体的激活，促进了M2巨噬细胞极化并抑制了炎症反应。
本研究得出结论，pMSCs通过抑制M1巨噬细胞极化和促炎因子分泌，同时促进M2巨噬细胞极化，减轻了LPS诱导的ALI模型中的肺损伤。这种作用是通过IL-10/STAT3/NLRP3轴介导的，为ALI治疗提供了一条新的治疗途径。
