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Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation

The abilities of cancer-associated fibroblasts (CAFs) to regulate immune responses in the context of radiotherapy remain largely unknown. This study was undertaken to determine whether ionizing radiation alters the CAF-mediated immunoregulatory effects on macrophages. CAFs were isolated from freshly...

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Autores principales: Berzaghi, Rodrigo, Ahktar, Muhammad Asad, Islam, Ashraful, Pedersen, Brede D., Hellevik, Turid, Martinez-Zubiaurre, Inigo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562631/
https://www.ncbi.nlm.nih.gov/pubmed/31108906
http://dx.doi.org/10.3390/cancers11050689
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author Berzaghi, Rodrigo
Ahktar, Muhammad Asad
Islam, Ashraful
Pedersen, Brede D.
Hellevik, Turid
Martinez-Zubiaurre, Inigo
author_facet Berzaghi, Rodrigo
Ahktar, Muhammad Asad
Islam, Ashraful
Pedersen, Brede D.
Hellevik, Turid
Martinez-Zubiaurre, Inigo
author_sort Berzaghi, Rodrigo
collection PubMed
description The abilities of cancer-associated fibroblasts (CAFs) to regulate immune responses in the context of radiotherapy remain largely unknown. This study was undertaken to determine whether ionizing radiation alters the CAF-mediated immunoregulatory effects on macrophages. CAFs were isolated from freshly-resected non-small cell lung cancer tumors, while monocyte-derived macrophages were prepared from peripheral blood of healthy donors. Experimental settings included both (CAF-macrophage) co-cultures and incubations of M0 and M1-macrophages in the presence of CAF-conditioned medium (CAF-CM). Functional assays to study macrophage polarization/activation included the expression of cell surface markers, production of nitric oxide, secretion of inflammatory cytokines and migratory capacity. We show that CAFs promote changes in M0-macrophages that harmonize with both M1-and M2-phenotypes. Additionally, CAFs inhibit pro-inflammatory features of M1-macrophages by reducing nitric oxide production, pro-inflammatory cytokines, migration, and M1-surface markers expression. Radiation delivered as single-high dose or in fractioned regimens did not modify the immunoregulatory features exerted by CAFs over macrophages in vitro. Protein expression analyses of CAF supernatants showed that irradiated and non-irradiated CAFs produce approximately the same protein levels of immunoregulators. Thus, CAF-derived soluble factors mediate measurable changes on uncommitted macrophages and down-regulate pro-inflammatory features of M1-polarized macrophages. Notably, ionizing radiation does not curtail the CAF-mediated immunosuppressive effects.
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spelling pubmed-65626312019-06-17 Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation Berzaghi, Rodrigo Ahktar, Muhammad Asad Islam, Ashraful Pedersen, Brede D. Hellevik, Turid Martinez-Zubiaurre, Inigo Cancers (Basel) Article The abilities of cancer-associated fibroblasts (CAFs) to regulate immune responses in the context of radiotherapy remain largely unknown. This study was undertaken to determine whether ionizing radiation alters the CAF-mediated immunoregulatory effects on macrophages. CAFs were isolated from freshly-resected non-small cell lung cancer tumors, while monocyte-derived macrophages were prepared from peripheral blood of healthy donors. Experimental settings included both (CAF-macrophage) co-cultures and incubations of M0 and M1-macrophages in the presence of CAF-conditioned medium (CAF-CM). Functional assays to study macrophage polarization/activation included the expression of cell surface markers, production of nitric oxide, secretion of inflammatory cytokines and migratory capacity. We show that CAFs promote changes in M0-macrophages that harmonize with both M1-and M2-phenotypes. Additionally, CAFs inhibit pro-inflammatory features of M1-macrophages by reducing nitric oxide production, pro-inflammatory cytokines, migration, and M1-surface markers expression. Radiation delivered as single-high dose or in fractioned regimens did not modify the immunoregulatory features exerted by CAFs over macrophages in vitro. Protein expression analyses of CAF supernatants showed that irradiated and non-irradiated CAFs produce approximately the same protein levels of immunoregulators. Thus, CAF-derived soluble factors mediate measurable changes on uncommitted macrophages and down-regulate pro-inflammatory features of M1-polarized macrophages. Notably, ionizing radiation does not curtail the CAF-mediated immunosuppressive effects. MDPI 2019-05-17 /pmc/articles/PMC6562631/ /pubmed/31108906 http://dx.doi.org/10.3390/cancers11050689 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Berzaghi, Rodrigo
Ahktar, Muhammad Asad
Islam, Ashraful
Pedersen, Brede D.
Hellevik, Turid
Martinez-Zubiaurre, Inigo
Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation
title Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation
title_full Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation
title_fullStr Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation
title_full_unstemmed Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation
title_short Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation
title_sort fibroblast-mediated immunoregulation of macrophage function is maintained after irradiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562631/
https://www.ncbi.nlm.nih.gov/pubmed/31108906
http://dx.doi.org/10.3390/cancers11050689
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