Cargando…
Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion
BACKGROUND: 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 inflammatio...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9590182/ https://www.ncbi.nlm.nih.gov/pubmed/36274148 http://dx.doi.org/10.1186/s12931-022-02210-7 |
_version_ | 1784814459358806016 |
---|---|
author | Shao, Feng-Jin Guo, Xiao-Ling Xu, Jia-Xue Liu, Rui Li, Dan-Yue Li, Qing-Hao Zhou, Ting Fang, Cun Tan, Xun |
author_facet | Shao, Feng-Jin Guo, Xiao-Ling Xu, Jia-Xue Liu, Rui Li, Dan-Yue Li, Qing-Hao Zhou, Ting Fang, Cun Tan, Xun |
author_sort | Shao, Feng-Jin |
collection | PubMed |
description | BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-022-02210-7. |
format | Online Article Text |
id | pubmed-9590182 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-95901822022-10-25 Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion Shao, Feng-Jin Guo, Xiao-Ling Xu, Jia-Xue Liu, Rui Li, Dan-Yue Li, Qing-Hao Zhou, Ting Fang, Cun Tan, Xun Respir Res Research BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-022-02210-7. BioMed Central 2022-10-23 2022 /pmc/articles/PMC9590182/ /pubmed/36274148 http://dx.doi.org/10.1186/s12931-022-02210-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Shao, Feng-Jin Guo, Xiao-Ling Xu, Jia-Xue Liu, Rui Li, Dan-Yue Li, Qing-Hao Zhou, Ting Fang, Cun Tan, Xun Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion |
title | Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion |
title_full | Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion |
title_fullStr | Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion |
title_full_unstemmed | Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion |
title_short | Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion |
title_sort | potential contribution of early endothelial progenitor cell (eepc)-to-macrophage switching in the development of pulmonary plexogenic lesion |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9590182/ https://www.ncbi.nlm.nih.gov/pubmed/36274148 http://dx.doi.org/10.1186/s12931-022-02210-7 |
work_keys_str_mv | AT shaofengjin potentialcontributionofearlyendothelialprogenitorcelleepctomacrophageswitchinginthedevelopmentofpulmonaryplexogeniclesion AT guoxiaoling potentialcontributionofearlyendothelialprogenitorcelleepctomacrophageswitchinginthedevelopmentofpulmonaryplexogeniclesion AT xujiaxue potentialcontributionofearlyendothelialprogenitorcelleepctomacrophageswitchinginthedevelopmentofpulmonaryplexogeniclesion AT liurui potentialcontributionofearlyendothelialprogenitorcelleepctomacrophageswitchinginthedevelopmentofpulmonaryplexogeniclesion AT lidanyue potentialcontributionofearlyendothelialprogenitorcelleepctomacrophageswitchinginthedevelopmentofpulmonaryplexogeniclesion AT liqinghao potentialcontributionofearlyendothelialprogenitorcelleepctomacrophageswitchinginthedevelopmentofpulmonaryplexogeniclesion AT zhouting potentialcontributionofearlyendothelialprogenitorcelleepctomacrophageswitchinginthedevelopmentofpulmonaryplexogeniclesion AT fangcun potentialcontributionofearlyendothelialprogenitorcelleepctomacrophageswitchinginthedevelopmentofpulmonaryplexogeniclesion AT tanxun potentialcontributionofearlyendothelialprogenitorcelleepctomacrophageswitchinginthedevelopmentofpulmonaryplexogeniclesion |