Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion.
Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion.
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早期内皮祖细胞（eEPC）向巨噬细胞转换在肺丛发生病变发展中的潜在贡献
DOI：
10.1186/s12931-022-02210-7
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发表时间：
2022-10-23
影响因子：
5.8
通讯作者：
中科院分区：
文献类型：
--
作者：
丛状病变在结构和细胞组成上具有动态外观，是人类严重肺动脉高压的组织学标志。病变发展的发病机制在很大程度上仍然未知，尽管它可能与局部炎症和早期祖内皮细胞（eEPCs）功能障碍有关。我们检验了eEPCs通过在慢性炎症环境中分化为巨噬细胞而促进丛状病变发展的假设。采用免疫组织化学方法检测了肉鸡丛状病变中eEPC标志物CD133和VEGFR-2、巨噬细胞系标志物甘露糖受体C-type 1（MRC1）、TNF α和核因子红细胞2相关因子2（Nrf2）的表达。用TNF α处理外周血单个核细胞来源的eEPCs，通过吞噬实验和Matrigel plug实验分别检测其巨噬细胞分化和血管生成能力。还评价了Nrf2在eEPC向巨噬细胞转化以及在MRC1表达中的作用。采用肿瘤坏死因子α（TNF α）腔内注射，观察局部炎症对丛状病变形成的影响。由早期病变组成的细胞具有典型的eEPC表型，而那些在更成熟的病变中显示巨噬细胞的分子和形态特征。随着病变进展，观察到丛状病变中TNF α产生增加。体外研究表明，慢性TNF α刺激可诱导eEPCs向巨噬细胞分化，并伴有应激反应转录因子Nrf2的过度激活。Nrf2激活（Keap1敲低）导致CD133显著下调，但MRC1 mRNA上调。双荧光素酶报告基因分析表明Nrf2与MRC1的启动子结合，从而触发其表达。与体外观察结果一致，TNF α暴露诱导Matrigel栓塞中eEPCs的巨噬细胞分化，导致栓塞的新血管形成减少。肿瘤坏死因子α的植入导致丛状病变密度显著增加。这项工作提供的证据表明，由慢性炎症刺激引起的eEPCs的巨噬细胞分化有助于丛状病变的发展。鉴于Nrf2在eEPCs向巨噬细胞的表型转换中的关键作用，靶向该分子可能有利于丛状病变的干预。在线版本包含补充材料，可通过10.1186/s12931 - 022 - 02210 - 7获得。
Plexiform lesions, which have a dynamic appearance in structure and cellular composition, are the histological hallmark of severe pulmonary arterial hypertension in humans. The pathogenesis of the lesion development remains largely unknown, although it may be related to local inflammation and dysfunction in early progenitor endothelial cells (eEPCs). We tested the hypothesis that eEPCs contribute to the development of plexiform lesions by differentiating into macrophages in the setting of chronic inflammation. The eEPC markers CD133 and VEGFR-2, macrophage lineage marker mannose receptor C-type 1 (MRC1), TNFα and nuclear factor erythroid 2-related factor 2 (Nrf2) in plexiform lesions in a broiler model were determined by immunohistochemistry. eEPCs derived from peripheral blood mononuclear cells were exposed to TNFα, and macrophage differentiation and angiogenic capacity of the cells were evaluated by phagocytotic and Matrigel plug assays, respectively. The role of Nrf2 in eEPC-to-macrophage transition as well as in MRC1 expression was also evaluated. Intratracheal installation of TNFα was conducted to determine the effect of local inflammation on the formation of plexiform lesions. Cells composed of the early lesions have a typical eEPC phenotype whereas those in more mature lesions display molecular and morphological characteristics of macrophages. Increased TNFα production in plexiform lesions was observed with lesion progression. In vitro studies showed that chronic TNFα challenge directed eEPCs to macrophage differentiation accompanied by hyperactivation of Nrf2, a stress-responsive transcription factor. Nrf2 activation (Keap1 knockdown) caused a marked downregulation in CD133 but upregulation in MRC1 mRNA. Dual luciferase reporter assay demonstrated that Nrf2 binds to the promoter of MRC1 to trigger its expression. In good agreement with the in vitro observation, TNFα exposure induced macrophage differentiation of eEPCs in Matrigel plugs, resulting in reduced neovascularization of the plugs. Intratracheal installation of TNFα resulted in a significant increase in plexiform lesion density. This work provides evidence suggesting that macrophage differentiation of eEPCs resulting from chronic inflammatory stimulation contributes to the development of plexiform lesions. Given the key role of Nrf2 in the phenotypic switching of eEPCs to macrophages, targeting this molecular might be beneficial for intervention of plexiform lesions. The online version contains supplementary material available at 10.1186/s12931-022-02210-7.
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影响因子：
16
作者：
Kim, You-Sun;Morgan, Michael J.;Liu, Zheng-Gang
通讯作者：
Liu, Zheng-Gang
DOI：
10.1164/rccm.201607-1515pp
发表时间：
2017-03-01
影响因子：
24.7
作者：
Bonnet, Sebastien;Provencher, Steeve;Humbert, Marc
通讯作者：
Humbert, Marc
影响因子：
4.4
作者：
Forman, MF;Wiedeman, RF
通讯作者：
Wiedeman, RF
影响因子：
9.6
作者：
Jones, Carla P.;Rankin, Sara M.
通讯作者：
Rankin, Sara M.
DOI：
10.1007/s00018-016-2223-0
发表时间：
2016-09
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Loboda A;Damulewicz M;Pyza E;Jozkowicz A;Dulak J
通讯作者：
Dulak J