Purpose

Emerging evidence has suggested the functions of exosomes in allergic diseases including asthma. This work aimed to study the roles of M2 macrophage-derived exosomes (M2Φ-Exos) in pediatric asthma progression and the potential molecules.

Methods

A mouse model with asthma was induced by ovalbumin (OVA) and treated with M2Φ-Exos. The secretion of inflammatory cytokines, fibrosis and inflammatory cell infiltration in mouse lung tissues were determined. The number of granulocytes in bronchoalveolar lavage fluid was measured. Airway epithelial cells (AECs) were treated with PDGF-BB for in vitro experiments. Proliferation, invasion, migration abilities and the expression of inflammation- and fibrosis-related factors in AECs were detected. Differentially expressed miRNAs after M2Φ-Exo treatment were screened out using a miRNA microarray. Targeting mRNAs of miR-370 were predicted on bioinformatics systems. Altered expression of miR-370 or FGF1 was introduced in mouse and cell models to validate their functions in asthma progression.

Results

M2Φ-Exos significantly alleviated OVA-induced fibrosis and inflammatory responses in mouse lung tissues, and inhibited abnormal proliferation and invasion, and fibrosis-related cytokine production in PDGF-BB-treated AECs. miR-370 was significantly upregulated after M2-exo treatment. FGF1 was identified as a target of miR-370. Knockdown of miR-370 or overexpression of FGF1 blocked the protective roles of M2Φ-Exos in mouse and cell models. M2Φ-Exos were found to inactivate the MAPK signaling pathway, which was recovered by further miR-370 inhibition or FGF1 overexpression.

Conclusion

M2Φ-Exos carry miR-370 to alleviate asthma progression through downregulating FGF1 and the MAPK/STAT1 signaling pathway. This study may offer novel insights into asthma treatment.

中文翻译：

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M2巨噬细胞衍生的外泌体携带microRNA-370通过抑制FGF1 / MAPK / STAT1轴来减轻哮喘的进展。

目的

越来越多的证据表明外泌体在包括哮喘在内的过敏性疾病中的功能。这项工作旨在研究M2巨噬细胞源性外泌体（M2Φ-Exos）在小儿哮喘进展中的作用及其潜在分子。

方法

卵白蛋白（OVA）诱导哮喘小鼠模型并用M2Φ-Exos治疗。确定了小鼠肺组织中炎性细胞因子的分泌，纤维化和炎性细胞浸润。测量支气管肺泡灌洗液中的粒细胞数目。用PDGF-BB处理气道上皮细胞（AEC）以进行体外实验。检测了AECs的增殖，侵袭，迁移能力以及炎症和纤维化相关因子的表达。使用miRNA微阵列筛选出M2Φ-Exo处理后差异表达的miRNA。在生物信息学系统上预测了miR-370的靶向mRNA。将miR-370或FGF1的表达改变引入小鼠和细胞模型，以验证其在哮喘进展中的功能。

结果

M2Φ-Exos显着减轻了OVA诱导的小鼠肺组织中的纤维化和炎症反应，并抑制了PDGF-BB处理的AEC中异常增殖和侵袭以及与纤维化相关的细胞因子的产生。M2-exo处理后，miR-370明显上调。FGF1被确定为miR-370的靶标。抑制miR-370或FGF1的过度表达可阻断M2Φ-Exos在小鼠和细胞模型中的保护作用。发现M2Φ-Exos使MAPK信号通路失活，该信号通路通过进一步的miR-370抑制或FGF1过表达得以恢复。

结论

M2Φ-Exos携带miR-370通过下调FGF1和MAPK / STAT1信号通路来缓解哮喘的进展。这项研究可能为哮喘治疗提供新的见解。