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....
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2020-02-01
|
Series: | PLoS Computational Biology |
Online Access: | https://doi.org/10.1371/journal.pcbi.1007657 |
id |
doaj-4bba50c0a81b451b884c8ed48721d89e |
---|---|
record_format |
Article |
spelling |
doaj-4bba50c0a81b451b884c8ed48721d89e2021-04-21T15:13:42ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582020-02-01162e100765710.1371/journal.pcbi.1007657Reprogramming of macrophages employing gene regulatory and metabolic network models.Franziska HörholdDavid EiselMarcus OswaldAmol KolteDaniela RöllWolfram OsenStefan B EichmüllerRainer KönigUpon 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.https://doi.org/10.1371/journal.pcbi.1007657 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Franziska Hörhold David Eisel Marcus Oswald Amol Kolte Daniela Röll Wolfram Osen Stefan B Eichmüller Rainer König |
spellingShingle |
Franziska Hörhold David Eisel Marcus Oswald Amol Kolte Daniela Röll Wolfram Osen Stefan B Eichmüller Rainer König Reprogramming of macrophages employing gene regulatory and metabolic network models. PLoS Computational Biology |
author_facet |
Franziska Hörhold David Eisel Marcus Oswald Amol Kolte Daniela Röll Wolfram Osen Stefan B Eichmüller Rainer König |
author_sort |
Franziska Hörhold |
title |
Reprogramming of macrophages employing gene regulatory and metabolic network models. |
title_short |
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_sort |
reprogramming of macrophages employing gene regulatory and metabolic network models. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Computational Biology |
issn |
1553-734X 1553-7358 |
publishDate |
2020-02-01 |
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. |
url |
https://doi.org/10.1371/journal.pcbi.1007657 |
work_keys_str_mv |
AT franziskahorhold reprogrammingofmacrophagesemployinggeneregulatoryandmetabolicnetworkmodels AT davideisel reprogrammingofmacrophagesemployinggeneregulatoryandmetabolicnetworkmodels AT marcusoswald reprogrammingofmacrophagesemployinggeneregulatoryandmetabolicnetworkmodels AT amolkolte reprogrammingofmacrophagesemployinggeneregulatoryandmetabolicnetworkmodels AT danielaroll reprogrammingofmacrophagesemployinggeneregulatoryandmetabolicnetworkmodels AT wolframosen reprogrammingofmacrophagesemployinggeneregulatoryandmetabolicnetworkmodels AT stefanbeichmuller reprogrammingofmacrophagesemployinggeneregulatoryandmetabolicnetworkmodels AT rainerkonig reprogrammingofmacrophagesemployinggeneregulatoryandmetabolicnetworkmodels |
_version_ |
1714667634444730368 |