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Cell-Crossing Functional Network Driven by microRNA-125a Regulates Endothelial Permeability and Monocyte Trafficking in Acute Inflammation

Opening of the endothelial barrier and targeted infiltration of leukocytes into the affected tissue are hallmarks of the inflammatory response. The molecular mechanisms regulating these processes are still widely elusive. In this study, we elucidate a novel regulatory network, in which miR-125a acts...

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Autores principales: Müller, Martin Bernhard, Hübner, Max, Li, Lei, Tomasi, Stephanie, Ließke, Valena, Effinger, David, Hirschberger, Simon, Pogoda, Kristin, Sperandio, Markus, Kreth, Simone
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986987/
https://www.ncbi.nlm.nih.gov/pubmed/35401562
http://dx.doi.org/10.3389/fimmu.2022.826047
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author Müller, Martin Bernhard
Hübner, Max
Li, Lei
Tomasi, Stephanie
Ließke, Valena
Effinger, David
Hirschberger, Simon
Pogoda, Kristin
Sperandio, Markus
Kreth, Simone
author_facet Müller, Martin Bernhard
Hübner, Max
Li, Lei
Tomasi, Stephanie
Ließke, Valena
Effinger, David
Hirschberger, Simon
Pogoda, Kristin
Sperandio, Markus
Kreth, Simone
author_sort Müller, Martin Bernhard
collection PubMed
description Opening of the endothelial barrier and targeted infiltration of leukocytes into the affected tissue are hallmarks of the inflammatory response. The molecular mechanisms regulating these processes are still widely elusive. In this study, we elucidate a novel regulatory network, in which miR-125a acts as a central hub that regulates and synchronizes both endothelial barrier permeability and monocyte migration. We found that inflammatory stimulation of endothelial cells induces miR-125a expression, which consecutively inhibits a regulatory network consisting of the two adhesion molecules VE-Cadherin (CDH5) and Claudin-5 (CLDN5), two regulatory tyrosine phosphatases (PTPN1, PPP1CA) and the transcription factor ETS1 eventually leading to the opening of the endothelial barrier. Moreover, under the influence of miR-125a, endothelial expression of the chemokine CCL2, the most predominant ligand for the monocytic chemokine receptor CCR2, was strongly enhanced. In monocytes, on the other hand, we detected markedly repressed expression levels of miR-125a upon inflammatory stimulation. This induced a forced expression of its direct target gene CCR2, entailing a strongly enhanced monocyte chemotaxis. Collectively, cell-type-specific differential expression of miR-125a forms a synergistic functional network controlling monocyte trafficking across the endothelial barrier towards the site of inflammation. In addition to the known mechanism of miRNAs being shuttled between cells via extracellular vesicles, our study uncovers a novel dimension of miRNA function: One miRNA, although disparately regulated in the cells involved, directs a biologic process in a synergistic and mutually reinforcing manner. These findings provide important new insights into the regulation of the inflammatory cascade and may be of great use for future clinical applications.
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spelling pubmed-89869872022-04-08 Cell-Crossing Functional Network Driven by microRNA-125a Regulates Endothelial Permeability and Monocyte Trafficking in Acute Inflammation Müller, Martin Bernhard Hübner, Max Li, Lei Tomasi, Stephanie Ließke, Valena Effinger, David Hirschberger, Simon Pogoda, Kristin Sperandio, Markus Kreth, Simone Front Immunol Immunology Opening of the endothelial barrier and targeted infiltration of leukocytes into the affected tissue are hallmarks of the inflammatory response. The molecular mechanisms regulating these processes are still widely elusive. In this study, we elucidate a novel regulatory network, in which miR-125a acts as a central hub that regulates and synchronizes both endothelial barrier permeability and monocyte migration. We found that inflammatory stimulation of endothelial cells induces miR-125a expression, which consecutively inhibits a regulatory network consisting of the two adhesion molecules VE-Cadherin (CDH5) and Claudin-5 (CLDN5), two regulatory tyrosine phosphatases (PTPN1, PPP1CA) and the transcription factor ETS1 eventually leading to the opening of the endothelial barrier. Moreover, under the influence of miR-125a, endothelial expression of the chemokine CCL2, the most predominant ligand for the monocytic chemokine receptor CCR2, was strongly enhanced. In monocytes, on the other hand, we detected markedly repressed expression levels of miR-125a upon inflammatory stimulation. This induced a forced expression of its direct target gene CCR2, entailing a strongly enhanced monocyte chemotaxis. Collectively, cell-type-specific differential expression of miR-125a forms a synergistic functional network controlling monocyte trafficking across the endothelial barrier towards the site of inflammation. In addition to the known mechanism of miRNAs being shuttled between cells via extracellular vesicles, our study uncovers a novel dimension of miRNA function: One miRNA, although disparately regulated in the cells involved, directs a biologic process in a synergistic and mutually reinforcing manner. These findings provide important new insights into the regulation of the inflammatory cascade and may be of great use for future clinical applications. Frontiers Media S.A. 2022-03-24 /pmc/articles/PMC8986987/ /pubmed/35401562 http://dx.doi.org/10.3389/fimmu.2022.826047 Text en Copyright © 2022 Müller, Hübner, Li, Tomasi, Ließke, Effinger, Hirschberger, Pogoda, Sperandio and Kreth https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Müller, Martin Bernhard
Hübner, Max
Li, Lei
Tomasi, Stephanie
Ließke, Valena
Effinger, David
Hirschberger, Simon
Pogoda, Kristin
Sperandio, Markus
Kreth, Simone
Cell-Crossing Functional Network Driven by microRNA-125a Regulates Endothelial Permeability and Monocyte Trafficking in Acute Inflammation
title Cell-Crossing Functional Network Driven by microRNA-125a Regulates Endothelial Permeability and Monocyte Trafficking in Acute Inflammation
title_full Cell-Crossing Functional Network Driven by microRNA-125a Regulates Endothelial Permeability and Monocyte Trafficking in Acute Inflammation
title_fullStr Cell-Crossing Functional Network Driven by microRNA-125a Regulates Endothelial Permeability and Monocyte Trafficking in Acute Inflammation
title_full_unstemmed Cell-Crossing Functional Network Driven by microRNA-125a Regulates Endothelial Permeability and Monocyte Trafficking in Acute Inflammation
title_short Cell-Crossing Functional Network Driven by microRNA-125a Regulates Endothelial Permeability and Monocyte Trafficking in Acute Inflammation
title_sort cell-crossing functional network driven by microrna-125a regulates endothelial permeability and monocyte trafficking in acute inflammation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986987/
https://www.ncbi.nlm.nih.gov/pubmed/35401562
http://dx.doi.org/10.3389/fimmu.2022.826047
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