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Dysregulation of Metabolic Pathways in Circulating Natural Killer Cells Isolated from Inflammatory Bowel Disease Patients

BACKGROUND AND AIMS: Inflammatory bowel diseases [IBD], comprising Crohn’s disease [CD] and ulcerative colitis [UC], are chronic conditions characterized by severe dysregulation of innate and adaptive immunity resulting in the destruction of the intestinal mucosa. Natural killer [NK] cells play a pi...

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Autores principales: Zaiatz Bittencourt, Vanessa, Jones, Fiona, Tosetto, Miriam, Doherty, Glen A, Ryan, Elizabeth J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328302/
https://www.ncbi.nlm.nih.gov/pubmed/33460436
http://dx.doi.org/10.1093/ecco-jcc/jjab014
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author Zaiatz Bittencourt, Vanessa
Jones, Fiona
Tosetto, Miriam
Doherty, Glen A
Ryan, Elizabeth J
author_facet Zaiatz Bittencourt, Vanessa
Jones, Fiona
Tosetto, Miriam
Doherty, Glen A
Ryan, Elizabeth J
author_sort Zaiatz Bittencourt, Vanessa
collection PubMed
description BACKGROUND AND AIMS: Inflammatory bowel diseases [IBD], comprising Crohn’s disease [CD] and ulcerative colitis [UC], are chronic conditions characterized by severe dysregulation of innate and adaptive immunity resulting in the destruction of the intestinal mucosa. Natural killer [NK] cells play a pivotal role in the dynamic interaction between the innate and adaptive immune response. There is an increasing appreciation for the key role immunometabolism plays in the regulation of NK cell function, yet little remains known about the metabolic profile, cytokine secretion, and killing capacity of human NK cells during active IBD. METHODS: Peripheral blood mononuclear cells were isolated from peripheral blood of patients with moderate to severely active IBD and healthy controls. NK cells were stained with a combination of cell surface receptors, intracellular cytokines, and proteins and analyzed by flow cytometry. For measurements of NK cell cytotoxicity, the calcein-AM release assay was performed. The metabolic profile was analyzed by an extracellular flux analyzer. RESULTS: NK cells from IBD patients produce large quantities of pro-inflammatory cytokines, IL-17A and TNF-α ex vivo, but have limited killing capability. Furthermore, patient NK cells have reduced mitochondrial mass and oxidative phosphorylation. mTORC1, an important cell and metabolic regulator, demonstrated limited activity in both freshly isolated cells and cytokine-stimulated cells. CONCLUSIONS: Our results demonstrate that circulating NK cells of IBD patients have an unbalanced metabolic profile, with faulty mitochondria and reduced capacity to kill. These aberrations in NK cell metabolism may contribute to defective killing and thus the secondary infections and increased risk of cancer observed in IBD patients.
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spelling pubmed-83283022021-08-03 Dysregulation of Metabolic Pathways in Circulating Natural Killer Cells Isolated from Inflammatory Bowel Disease Patients Zaiatz Bittencourt, Vanessa Jones, Fiona Tosetto, Miriam Doherty, Glen A Ryan, Elizabeth J J Crohns Colitis Original Articles BACKGROUND AND AIMS: Inflammatory bowel diseases [IBD], comprising Crohn’s disease [CD] and ulcerative colitis [UC], are chronic conditions characterized by severe dysregulation of innate and adaptive immunity resulting in the destruction of the intestinal mucosa. Natural killer [NK] cells play a pivotal role in the dynamic interaction between the innate and adaptive immune response. There is an increasing appreciation for the key role immunometabolism plays in the regulation of NK cell function, yet little remains known about the metabolic profile, cytokine secretion, and killing capacity of human NK cells during active IBD. METHODS: Peripheral blood mononuclear cells were isolated from peripheral blood of patients with moderate to severely active IBD and healthy controls. NK cells were stained with a combination of cell surface receptors, intracellular cytokines, and proteins and analyzed by flow cytometry. For measurements of NK cell cytotoxicity, the calcein-AM release assay was performed. The metabolic profile was analyzed by an extracellular flux analyzer. RESULTS: NK cells from IBD patients produce large quantities of pro-inflammatory cytokines, IL-17A and TNF-α ex vivo, but have limited killing capability. Furthermore, patient NK cells have reduced mitochondrial mass and oxidative phosphorylation. mTORC1, an important cell and metabolic regulator, demonstrated limited activity in both freshly isolated cells and cytokine-stimulated cells. CONCLUSIONS: Our results demonstrate that circulating NK cells of IBD patients have an unbalanced metabolic profile, with faulty mitochondria and reduced capacity to kill. These aberrations in NK cell metabolism may contribute to defective killing and thus the secondary infections and increased risk of cancer observed in IBD patients. Oxford University Press 2021-01-18 /pmc/articles/PMC8328302/ /pubmed/33460436 http://dx.doi.org/10.1093/ecco-jcc/jjab014 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Articles
Zaiatz Bittencourt, Vanessa
Jones, Fiona
Tosetto, Miriam
Doherty, Glen A
Ryan, Elizabeth J
Dysregulation of Metabolic Pathways in Circulating Natural Killer Cells Isolated from Inflammatory Bowel Disease Patients
title Dysregulation of Metabolic Pathways in Circulating Natural Killer Cells Isolated from Inflammatory Bowel Disease Patients
title_full Dysregulation of Metabolic Pathways in Circulating Natural Killer Cells Isolated from Inflammatory Bowel Disease Patients
title_fullStr Dysregulation of Metabolic Pathways in Circulating Natural Killer Cells Isolated from Inflammatory Bowel Disease Patients
title_full_unstemmed Dysregulation of Metabolic Pathways in Circulating Natural Killer Cells Isolated from Inflammatory Bowel Disease Patients
title_short Dysregulation of Metabolic Pathways in Circulating Natural Killer Cells Isolated from Inflammatory Bowel Disease Patients
title_sort dysregulation of metabolic pathways in circulating natural killer cells isolated from inflammatory bowel disease patients
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328302/
https://www.ncbi.nlm.nih.gov/pubmed/33460436
http://dx.doi.org/10.1093/ecco-jcc/jjab014
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