Cargando…

mTOR Senses Environmental Cues to Shape the Fibroblast-like Synoviocyte Response to Inflammation

Accumulating evidence suggests that metabolic master regulators, including mTOR, regulate adaptive and innate immune responses. Resident mesenchymal tissue components are increasingly recognized as key effector cells in inflammation. Whether mTOR also controls the inflammatory response in fibroblast...

Descripción completa

Detalles Bibliográficos
Autores principales: Karonitsch, Thomas, Kandasamy, Richard K., Kartnig, Felix, Herdy, Barbara, Dalwigk, Karolina, Niederreiter, Birgit, Holinka, Johannes, Sevelda, Florian, Windhager, Reinhard, Bilban, Martin, Weichhart, Thomas, Säemann, Marcus, Pap, Thomas, Steiner, Günter, Smolen, Josef S., Kiener, Hans P., Superti-Furga, Giulio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972226/
https://www.ncbi.nlm.nih.gov/pubmed/29768212
http://dx.doi.org/10.1016/j.celrep.2018.04.044
_version_ 1783326397514645504
author Karonitsch, Thomas
Kandasamy, Richard K.
Kartnig, Felix
Herdy, Barbara
Dalwigk, Karolina
Niederreiter, Birgit
Holinka, Johannes
Sevelda, Florian
Windhager, Reinhard
Bilban, Martin
Weichhart, Thomas
Säemann, Marcus
Pap, Thomas
Steiner, Günter
Smolen, Josef S.
Kiener, Hans P.
Superti-Furga, Giulio
author_facet Karonitsch, Thomas
Kandasamy, Richard K.
Kartnig, Felix
Herdy, Barbara
Dalwigk, Karolina
Niederreiter, Birgit
Holinka, Johannes
Sevelda, Florian
Windhager, Reinhard
Bilban, Martin
Weichhart, Thomas
Säemann, Marcus
Pap, Thomas
Steiner, Günter
Smolen, Josef S.
Kiener, Hans P.
Superti-Furga, Giulio
author_sort Karonitsch, Thomas
collection PubMed
description Accumulating evidence suggests that metabolic master regulators, including mTOR, regulate adaptive and innate immune responses. Resident mesenchymal tissue components are increasingly recognized as key effector cells in inflammation. Whether mTOR also controls the inflammatory response in fibroblasts is insufficiently studied. Here, we show that TNF signaling co-opts the mTOR pathway to shift synovial fibroblast (FLS) inflammation toward an IFN response. mTOR pathway activation is associated with decreased NF-κB-mediated gene expression (e.g., PTGS2, IL-6, and IL-8) but increased STAT1-dependent gene expression (e.g., CXCL11 and TNFSF13B). We further demonstrate how metabolic inputs, such as amino acids, impinge on TNF-mTORC1 signaling to differentially regulate pro-inflammatory signaling circuits. Our results define a critical role for mTOR in the regulation of the pro-inflammatory response in FLSs and unfold its pathogenic involvement in TNF-driven diseases, such as rheumatoid arthritis (RA).
format Online
Article
Text
id pubmed-5972226
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Cell Press
record_format MEDLINE/PubMed
spelling pubmed-59722262018-06-01 mTOR Senses Environmental Cues to Shape the Fibroblast-like Synoviocyte Response to Inflammation Karonitsch, Thomas Kandasamy, Richard K. Kartnig, Felix Herdy, Barbara Dalwigk, Karolina Niederreiter, Birgit Holinka, Johannes Sevelda, Florian Windhager, Reinhard Bilban, Martin Weichhart, Thomas Säemann, Marcus Pap, Thomas Steiner, Günter Smolen, Josef S. Kiener, Hans P. Superti-Furga, Giulio Cell Rep Article Accumulating evidence suggests that metabolic master regulators, including mTOR, regulate adaptive and innate immune responses. Resident mesenchymal tissue components are increasingly recognized as key effector cells in inflammation. Whether mTOR also controls the inflammatory response in fibroblasts is insufficiently studied. Here, we show that TNF signaling co-opts the mTOR pathway to shift synovial fibroblast (FLS) inflammation toward an IFN response. mTOR pathway activation is associated with decreased NF-κB-mediated gene expression (e.g., PTGS2, IL-6, and IL-8) but increased STAT1-dependent gene expression (e.g., CXCL11 and TNFSF13B). We further demonstrate how metabolic inputs, such as amino acids, impinge on TNF-mTORC1 signaling to differentially regulate pro-inflammatory signaling circuits. Our results define a critical role for mTOR in the regulation of the pro-inflammatory response in FLSs and unfold its pathogenic involvement in TNF-driven diseases, such as rheumatoid arthritis (RA). Cell Press 2018-05-15 /pmc/articles/PMC5972226/ /pubmed/29768212 http://dx.doi.org/10.1016/j.celrep.2018.04.044 Text en © 2018 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Karonitsch, Thomas
Kandasamy, Richard K.
Kartnig, Felix
Herdy, Barbara
Dalwigk, Karolina
Niederreiter, Birgit
Holinka, Johannes
Sevelda, Florian
Windhager, Reinhard
Bilban, Martin
Weichhart, Thomas
Säemann, Marcus
Pap, Thomas
Steiner, Günter
Smolen, Josef S.
Kiener, Hans P.
Superti-Furga, Giulio
mTOR Senses Environmental Cues to Shape the Fibroblast-like Synoviocyte Response to Inflammation
title mTOR Senses Environmental Cues to Shape the Fibroblast-like Synoviocyte Response to Inflammation
title_full mTOR Senses Environmental Cues to Shape the Fibroblast-like Synoviocyte Response to Inflammation
title_fullStr mTOR Senses Environmental Cues to Shape the Fibroblast-like Synoviocyte Response to Inflammation
title_full_unstemmed mTOR Senses Environmental Cues to Shape the Fibroblast-like Synoviocyte Response to Inflammation
title_short mTOR Senses Environmental Cues to Shape the Fibroblast-like Synoviocyte Response to Inflammation
title_sort mtor senses environmental cues to shape the fibroblast-like synoviocyte response to inflammation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972226/
https://www.ncbi.nlm.nih.gov/pubmed/29768212
http://dx.doi.org/10.1016/j.celrep.2018.04.044
work_keys_str_mv AT karonitschthomas mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT kandasamyrichardk mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT kartnigfelix mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT herdybarbara mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT dalwigkkarolina mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT niederreiterbirgit mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT holinkajohannes mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT seveldaflorian mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT windhagerreinhard mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT bilbanmartin mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT weichhartthomas mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT saemannmarcus mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT papthomas mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT steinergunter mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT smolenjosefs mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT kienerhansp mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation
AT supertifurgagiulio mtorsensesenvironmentalcuestoshapethefibroblastlikesynoviocyteresponsetoinflammation