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Reprogramming of macrophages employing gene regulatory and metabolic network models
Upon exposure to different stimuli, resting macrophages undergo classical or alternative polarization into distinct phenotypes that can cause fatal dysfunction in a large range of diseases, such as systemic infection leading to sepsis or the generation of an immunosuppressive tumor microenvironment....
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059956/ https://www.ncbi.nlm.nih.gov/pubmed/32097424 http://dx.doi.org/10.1371/journal.pcbi.1007657 |
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author | Hörhold, Franziska Eisel, David Oswald, Marcus Kolte, Amol Röll, Daniela Osen, Wolfram Eichmüller, Stefan B. König, Rainer |
author_facet | Hörhold, Franziska Eisel, David Oswald, Marcus Kolte, Amol Röll, Daniela Osen, Wolfram Eichmüller, Stefan B. König, Rainer |
author_sort | Hörhold, Franziska |
collection | PubMed |
description | Upon exposure to different stimuli, resting macrophages undergo classical or alternative polarization into distinct phenotypes that can cause fatal dysfunction in a large range of diseases, such as systemic infection leading to sepsis or the generation of an immunosuppressive tumor microenvironment. Investigating gene regulatory and metabolic networks, we observed two metabolic switches during polarization. Most prominently, anaerobic glycolysis was utilized by M1-polarized macrophages, while the biosynthesis of inosine monophosphate was upregulated in M2-polarized macrophages. Moreover, we observed a switch in the urea cycle. Gene regulatory network models revealed E2F1, MYC, PPARγ and STAT6 to be the major players in the distinct signatures of these polarization events. Employing functional assays targeting these regulators, we observed the repolarization of M2-like cells into M1-like cells, as evidenced by their specific gene expression signatures and cytokine secretion profiles. The predicted regulators are essential to maintaining the M2-like phenotype and function and thus represent potential targets for the therapeutic reprogramming of immunosuppressive M2-like macrophages. |
format | Online Article Text |
id | pubmed-7059956 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-70599562020-03-12 Reprogramming of macrophages employing gene regulatory and metabolic network models Hörhold, Franziska Eisel, David Oswald, Marcus Kolte, Amol Röll, Daniela Osen, Wolfram Eichmüller, Stefan B. König, Rainer PLoS Comput Biol Research Article Upon exposure to different stimuli, resting macrophages undergo classical or alternative polarization into distinct phenotypes that can cause fatal dysfunction in a large range of diseases, such as systemic infection leading to sepsis or the generation of an immunosuppressive tumor microenvironment. Investigating gene regulatory and metabolic networks, we observed two metabolic switches during polarization. Most prominently, anaerobic glycolysis was utilized by M1-polarized macrophages, while the biosynthesis of inosine monophosphate was upregulated in M2-polarized macrophages. Moreover, we observed a switch in the urea cycle. Gene regulatory network models revealed E2F1, MYC, PPARγ and STAT6 to be the major players in the distinct signatures of these polarization events. Employing functional assays targeting these regulators, we observed the repolarization of M2-like cells into M1-like cells, as evidenced by their specific gene expression signatures and cytokine secretion profiles. The predicted regulators are essential to maintaining the M2-like phenotype and function and thus represent potential targets for the therapeutic reprogramming of immunosuppressive M2-like macrophages. Public Library of Science 2020-02-25 /pmc/articles/PMC7059956/ /pubmed/32097424 http://dx.doi.org/10.1371/journal.pcbi.1007657 Text en © 2020 Hörhold et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Hörhold, Franziska Eisel, David Oswald, Marcus Kolte, Amol Röll, Daniela Osen, Wolfram Eichmüller, Stefan B. König, Rainer Reprogramming of macrophages employing gene regulatory and metabolic network models |
title | Reprogramming of macrophages employing gene regulatory and metabolic network models |
title_full | Reprogramming of macrophages employing gene regulatory and metabolic network models |
title_fullStr | Reprogramming of macrophages employing gene regulatory and metabolic network models |
title_full_unstemmed | Reprogramming of macrophages employing gene regulatory and metabolic network models |
title_short | Reprogramming of macrophages employing gene regulatory and metabolic network models |
title_sort | reprogramming of macrophages employing gene regulatory and metabolic network models |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059956/ https://www.ncbi.nlm.nih.gov/pubmed/32097424 http://dx.doi.org/10.1371/journal.pcbi.1007657 |
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