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The Impact of Phase-Specific Macrophage Depletion on Intestinal Anastomotic Healing

Intestinal anastomotic healing (AH) is critical in colorectal surgery, since disruptive AH leads to anastomotic leakage, a feared postoperative complication. Macrophages are innate immune cells and are instrumental in orchestrating intestinal wound healing, displaying a functional dichotomy as effec...

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Autores principales: Winter, Maximiliane, Heitplatz, Barbara, Koppers, Nils, Mohr, Annika, Bungert, Alexander D., Juratli, Mazen A., Strücker, Benjamin, Varga, Georg, Pascher, Andreas, Becker, Felix
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093464/
https://www.ncbi.nlm.nih.gov/pubmed/37048112
http://dx.doi.org/10.3390/cells12071039
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author Winter, Maximiliane
Heitplatz, Barbara
Koppers, Nils
Mohr, Annika
Bungert, Alexander D.
Juratli, Mazen A.
Strücker, Benjamin
Varga, Georg
Pascher, Andreas
Becker, Felix
author_facet Winter, Maximiliane
Heitplatz, Barbara
Koppers, Nils
Mohr, Annika
Bungert, Alexander D.
Juratli, Mazen A.
Strücker, Benjamin
Varga, Georg
Pascher, Andreas
Becker, Felix
author_sort Winter, Maximiliane
collection PubMed
description Intestinal anastomotic healing (AH) is critical in colorectal surgery, since disruptive AH leads to anastomotic leakage, a feared postoperative complication. Macrophages are innate immune cells and are instrumental in orchestrating intestinal wound healing, displaying a functional dichotomy as effectors of both tissue injury and repair. The aim of this study was to investigate the phase-specific function and plasticity of macrophages during intestinal AH. Transgenic CD11b diphtheria toxin receptor (CD11b-DTR) mice were used to deplete intestinal macrophages in a temporally controlled manner. Distal colonic end-to-end anastomoses were created in CD11b-DTR, and wild-type mice and macrophages were selectively depleted during either the inflammatory (day 0–3), proliferative (day 4–10), or reparative (day 11–20) phase of intestinal AH, respectively. For each time point, histological and functional analysis as well as gene set enrichment analysis (GSEA) of RNA-sequencing data were performed. Macrophage depletion during the inflammatory phase significantly reduced the associated inflammatory state without compromising microscopic AH. When intestinal macrophages were depleted during the proliferative phase, AH was improved, despite significantly reduced perianastomotic neoangiogenesis. Lastly, macrophages were depleted during the reparative phase and GSEA revealed macrophage-dependent pathways involved in collagen remodeling, cell proliferation, and extracellular matrix composition. However, AH remained comparable at this late timepoint. These results demonstrate that during intestinal AH, macrophages elicit phase-specific effects, and that therapeutic interventions must critically balance their dual and timely defined role.
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spelling pubmed-100934642023-04-13 The Impact of Phase-Specific Macrophage Depletion on Intestinal Anastomotic Healing Winter, Maximiliane Heitplatz, Barbara Koppers, Nils Mohr, Annika Bungert, Alexander D. Juratli, Mazen A. Strücker, Benjamin Varga, Georg Pascher, Andreas Becker, Felix Cells Article Intestinal anastomotic healing (AH) is critical in colorectal surgery, since disruptive AH leads to anastomotic leakage, a feared postoperative complication. Macrophages are innate immune cells and are instrumental in orchestrating intestinal wound healing, displaying a functional dichotomy as effectors of both tissue injury and repair. The aim of this study was to investigate the phase-specific function and plasticity of macrophages during intestinal AH. Transgenic CD11b diphtheria toxin receptor (CD11b-DTR) mice were used to deplete intestinal macrophages in a temporally controlled manner. Distal colonic end-to-end anastomoses were created in CD11b-DTR, and wild-type mice and macrophages were selectively depleted during either the inflammatory (day 0–3), proliferative (day 4–10), or reparative (day 11–20) phase of intestinal AH, respectively. For each time point, histological and functional analysis as well as gene set enrichment analysis (GSEA) of RNA-sequencing data were performed. Macrophage depletion during the inflammatory phase significantly reduced the associated inflammatory state without compromising microscopic AH. When intestinal macrophages were depleted during the proliferative phase, AH was improved, despite significantly reduced perianastomotic neoangiogenesis. Lastly, macrophages were depleted during the reparative phase and GSEA revealed macrophage-dependent pathways involved in collagen remodeling, cell proliferation, and extracellular matrix composition. However, AH remained comparable at this late timepoint. These results demonstrate that during intestinal AH, macrophages elicit phase-specific effects, and that therapeutic interventions must critically balance their dual and timely defined role. MDPI 2023-03-29 /pmc/articles/PMC10093464/ /pubmed/37048112 http://dx.doi.org/10.3390/cells12071039 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Winter, Maximiliane
Heitplatz, Barbara
Koppers, Nils
Mohr, Annika
Bungert, Alexander D.
Juratli, Mazen A.
Strücker, Benjamin
Varga, Georg
Pascher, Andreas
Becker, Felix
The Impact of Phase-Specific Macrophage Depletion on Intestinal Anastomotic Healing
title The Impact of Phase-Specific Macrophage Depletion on Intestinal Anastomotic Healing
title_full The Impact of Phase-Specific Macrophage Depletion on Intestinal Anastomotic Healing
title_fullStr The Impact of Phase-Specific Macrophage Depletion on Intestinal Anastomotic Healing
title_full_unstemmed The Impact of Phase-Specific Macrophage Depletion on Intestinal Anastomotic Healing
title_short The Impact of Phase-Specific Macrophage Depletion on Intestinal Anastomotic Healing
title_sort impact of phase-specific macrophage depletion on intestinal anastomotic healing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093464/
https://www.ncbi.nlm.nih.gov/pubmed/37048112
http://dx.doi.org/10.3390/cells12071039
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