Cargando…
Extensive blood transcriptome analysis reveals cellular signaling networks activated by circulating glycocalyx components reflecting vascular injury in COVID-19
BACKGROUND: Degradation of the endothelial protective glycocalyx layer during COVID-19 infection leads to shedding of major glycocalyx components. These circulating proteins and their degradation products may feedback on immune and endothelial cells and activate molecular signaling cascades in COVID...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909741/ https://www.ncbi.nlm.nih.gov/pubmed/36776845 http://dx.doi.org/10.3389/fimmu.2023.1129766 |
_version_ | 1784884638794121216 |
---|---|
author | Borrmann, Melanie Brandes, Florian Kirchner, Benedikt Klein, Matthias Billaud, Jean-Noël Reithmair, Marlene Rehm, Markus Schelling, Gustav Pfaffl, Michael W. Meidert, Agnes S. |
author_facet | Borrmann, Melanie Brandes, Florian Kirchner, Benedikt Klein, Matthias Billaud, Jean-Noël Reithmair, Marlene Rehm, Markus Schelling, Gustav Pfaffl, Michael W. Meidert, Agnes S. |
author_sort | Borrmann, Melanie |
collection | PubMed |
description | BACKGROUND: Degradation of the endothelial protective glycocalyx layer during COVID-19 infection leads to shedding of major glycocalyx components. These circulating proteins and their degradation products may feedback on immune and endothelial cells and activate molecular signaling cascades in COVID-19 associated microvascular injury. To test this hypothesis, we measured plasma glycocalyx components in patients with SARS-CoV-2 infection of variable disease severity and identified molecular signaling networks activated by glycocalyx components in immune and endothelial cells. METHODS: We studied patients with RT-PCR confirmed COVID-19 pneumonia, patients with COVID-19 Acute Respiratory Distress Syndrome (ARDS) and healthy controls (wildtype, n=20 in each group) and measured syndecan-1, heparan sulfate and hyaluronic acid. The in-silico construction of signaling networks was based on RNA sequencing (RNAseq) of mRNA transcripts derived from blood cells and of miRNAs isolated from extracellular vesicles from the identical cohort. Differentially regulated RNAs between groups were identified by gene expression analysis. Both RNAseq data sets were used for network construction of circulating glycosaminoglycans focusing on immune and endothelial cells. RESULTS: Plasma concentrations of glycocalyx components were highest in COVID-19 ARDS. Hyaluronic acid plasma levels in patients admitted with COVID-19 pneumonia who later developed ARDS during hospital treatment (n=8) were significantly higher at hospital admission than in patients with an early recovery. RNAseq identified hyaluronic acid as an upregulator of TLR4 in pneumonia and ARDS. In COVID-19 ARDS, syndecan-1 increased IL-6, which was significantly higher than in pneumonia. In ARDS, hyaluronic acid activated NRP1, a co-receptor of activated VEGFA, which is associated with pulmonary vascular hyperpermeability and interacted with VCAN (upregulated), a proteoglycan important for chemokine communication. CONCLUSIONS: Circulating glycocalyx components in COVID-19 have distinct biologic feedback effects on immune and endothelial cells and result in upregulation of key regulatory transcripts leading to further immune activation and more severe systemic inflammation. These consequences are most pronounced during the early hospital phase of COVID-19 before pulmonary failure develops. Elevated levels of circulating glycocalyx components may early identify patients at risk for microvascular injury and ARDS. The timely inhibition of glycocalyx degradation could provide a novel therapeutic approach to prevent the development of ARDS in COVID-19. |
format | Online Article Text |
id | pubmed-9909741 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99097412023-02-10 Extensive blood transcriptome analysis reveals cellular signaling networks activated by circulating glycocalyx components reflecting vascular injury in COVID-19 Borrmann, Melanie Brandes, Florian Kirchner, Benedikt Klein, Matthias Billaud, Jean-Noël Reithmair, Marlene Rehm, Markus Schelling, Gustav Pfaffl, Michael W. Meidert, Agnes S. Front Immunol Immunology BACKGROUND: Degradation of the endothelial protective glycocalyx layer during COVID-19 infection leads to shedding of major glycocalyx components. These circulating proteins and their degradation products may feedback on immune and endothelial cells and activate molecular signaling cascades in COVID-19 associated microvascular injury. To test this hypothesis, we measured plasma glycocalyx components in patients with SARS-CoV-2 infection of variable disease severity and identified molecular signaling networks activated by glycocalyx components in immune and endothelial cells. METHODS: We studied patients with RT-PCR confirmed COVID-19 pneumonia, patients with COVID-19 Acute Respiratory Distress Syndrome (ARDS) and healthy controls (wildtype, n=20 in each group) and measured syndecan-1, heparan sulfate and hyaluronic acid. The in-silico construction of signaling networks was based on RNA sequencing (RNAseq) of mRNA transcripts derived from blood cells and of miRNAs isolated from extracellular vesicles from the identical cohort. Differentially regulated RNAs between groups were identified by gene expression analysis. Both RNAseq data sets were used for network construction of circulating glycosaminoglycans focusing on immune and endothelial cells. RESULTS: Plasma concentrations of glycocalyx components were highest in COVID-19 ARDS. Hyaluronic acid plasma levels in patients admitted with COVID-19 pneumonia who later developed ARDS during hospital treatment (n=8) were significantly higher at hospital admission than in patients with an early recovery. RNAseq identified hyaluronic acid as an upregulator of TLR4 in pneumonia and ARDS. In COVID-19 ARDS, syndecan-1 increased IL-6, which was significantly higher than in pneumonia. In ARDS, hyaluronic acid activated NRP1, a co-receptor of activated VEGFA, which is associated with pulmonary vascular hyperpermeability and interacted with VCAN (upregulated), a proteoglycan important for chemokine communication. CONCLUSIONS: Circulating glycocalyx components in COVID-19 have distinct biologic feedback effects on immune and endothelial cells and result in upregulation of key regulatory transcripts leading to further immune activation and more severe systemic inflammation. These consequences are most pronounced during the early hospital phase of COVID-19 before pulmonary failure develops. Elevated levels of circulating glycocalyx components may early identify patients at risk for microvascular injury and ARDS. The timely inhibition of glycocalyx degradation could provide a novel therapeutic approach to prevent the development of ARDS in COVID-19. Frontiers Media S.A. 2023-01-26 /pmc/articles/PMC9909741/ /pubmed/36776845 http://dx.doi.org/10.3389/fimmu.2023.1129766 Text en Copyright © 2023 Borrmann, Brandes, Kirchner, Klein, Billaud, Reithmair, Rehm, Schelling, Pfaffl and Meidert 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 Borrmann, Melanie Brandes, Florian Kirchner, Benedikt Klein, Matthias Billaud, Jean-Noël Reithmair, Marlene Rehm, Markus Schelling, Gustav Pfaffl, Michael W. Meidert, Agnes S. Extensive blood transcriptome analysis reveals cellular signaling networks activated by circulating glycocalyx components reflecting vascular injury in COVID-19 |
title | Extensive blood transcriptome analysis reveals cellular signaling networks activated by circulating glycocalyx components reflecting vascular injury in COVID-19 |
title_full | Extensive blood transcriptome analysis reveals cellular signaling networks activated by circulating glycocalyx components reflecting vascular injury in COVID-19 |
title_fullStr | Extensive blood transcriptome analysis reveals cellular signaling networks activated by circulating glycocalyx components reflecting vascular injury in COVID-19 |
title_full_unstemmed | Extensive blood transcriptome analysis reveals cellular signaling networks activated by circulating glycocalyx components reflecting vascular injury in COVID-19 |
title_short | Extensive blood transcriptome analysis reveals cellular signaling networks activated by circulating glycocalyx components reflecting vascular injury in COVID-19 |
title_sort | extensive blood transcriptome analysis reveals cellular signaling networks activated by circulating glycocalyx components reflecting vascular injury in covid-19 |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909741/ https://www.ncbi.nlm.nih.gov/pubmed/36776845 http://dx.doi.org/10.3389/fimmu.2023.1129766 |
work_keys_str_mv | AT borrmannmelanie extensivebloodtranscriptomeanalysisrevealscellularsignalingnetworksactivatedbycirculatingglycocalyxcomponentsreflectingvascularinjuryincovid19 AT brandesflorian extensivebloodtranscriptomeanalysisrevealscellularsignalingnetworksactivatedbycirculatingglycocalyxcomponentsreflectingvascularinjuryincovid19 AT kirchnerbenedikt extensivebloodtranscriptomeanalysisrevealscellularsignalingnetworksactivatedbycirculatingglycocalyxcomponentsreflectingvascularinjuryincovid19 AT kleinmatthias extensivebloodtranscriptomeanalysisrevealscellularsignalingnetworksactivatedbycirculatingglycocalyxcomponentsreflectingvascularinjuryincovid19 AT billaudjeannoel extensivebloodtranscriptomeanalysisrevealscellularsignalingnetworksactivatedbycirculatingglycocalyxcomponentsreflectingvascularinjuryincovid19 AT reithmairmarlene extensivebloodtranscriptomeanalysisrevealscellularsignalingnetworksactivatedbycirculatingglycocalyxcomponentsreflectingvascularinjuryincovid19 AT rehmmarkus extensivebloodtranscriptomeanalysisrevealscellularsignalingnetworksactivatedbycirculatingglycocalyxcomponentsreflectingvascularinjuryincovid19 AT schellinggustav extensivebloodtranscriptomeanalysisrevealscellularsignalingnetworksactivatedbycirculatingglycocalyxcomponentsreflectingvascularinjuryincovid19 AT pfafflmichaelw extensivebloodtranscriptomeanalysisrevealscellularsignalingnetworksactivatedbycirculatingglycocalyxcomponentsreflectingvascularinjuryincovid19 AT meidertagness extensivebloodtranscriptomeanalysisrevealscellularsignalingnetworksactivatedbycirculatingglycocalyxcomponentsreflectingvascularinjuryincovid19 |