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NRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA
Background: CD4+ T cells critically contribute to the initiation and perturbation of inflammation. When CD4+ T cells enter inflamed tissues, they adapt to hypoxia and oxidative stress conditions, and to a reduction in nutrients. We aimed to investigate how this distinct environment regulates T cell...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9774972/ https://www.ncbi.nlm.nih.gov/pubmed/36552634 http://dx.doi.org/10.3390/antiox11122426 |
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author | Rajendiran, Anandhi Subramanyam, Sudheendra Hebbar Klemm, Patricia Jankowski, Vera van Loosdregt, Jorg Vastert, Bas Vollbach, Kristina Wagner, Norbert Tenbrock, Klaus Ohl, Kim |
author_facet | Rajendiran, Anandhi Subramanyam, Sudheendra Hebbar Klemm, Patricia Jankowski, Vera van Loosdregt, Jorg Vastert, Bas Vollbach, Kristina Wagner, Norbert Tenbrock, Klaus Ohl, Kim |
author_sort | Rajendiran, Anandhi |
collection | PubMed |
description | Background: CD4+ T cells critically contribute to the initiation and perturbation of inflammation. When CD4+ T cells enter inflamed tissues, they adapt to hypoxia and oxidative stress conditions, and to a reduction in nutrients. We aimed to investigate how this distinct environment regulates T cell responses within the inflamed joints of patients with childhood rheumatism (JIA) by analyzing the behavior of NRF2—the key regulator of the anti-oxidative stress response—and its signaling pathways. Methods: Flow cytometry and quantitative RT-PCR were used to perform metabolic profiling of T cells and to measure the production of inflammatory cytokines. Loss of function analyses were carried out by means of siRNA transfection experiments. NRF2 activation was induced by treatment with 4-octyl-Itaconate (4-OI). Results: Flow cytometry analyses revealed a high metabolic status in CD4+ T cells taken from synovial fluid (SF) with greater mitochondrial mass, and increased glucose and fatty acid uptake. This resulted in a heightened oxidative status of SF CD4+ T cells. Despite raised ROS levels, expression of NRF2 and its target gene NQO1 were lower in CD4+ T cells from SF than in those from blood. Indeed, NRF2 activation of CD4+ T cells downregulated oxidative stress markers, altered the metabolic phenotype and reduced secretion of IFN-γ. Conclusion: NRF2 could be a potential regulator in CD4+ T cells during chronic inflammation and could instigate a drift toward disease progression or regression, depending on the inflammatory environment. |
format | Online Article Text |
id | pubmed-9774972 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97749722022-12-23 NRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA Rajendiran, Anandhi Subramanyam, Sudheendra Hebbar Klemm, Patricia Jankowski, Vera van Loosdregt, Jorg Vastert, Bas Vollbach, Kristina Wagner, Norbert Tenbrock, Klaus Ohl, Kim Antioxidants (Basel) Article Background: CD4+ T cells critically contribute to the initiation and perturbation of inflammation. When CD4+ T cells enter inflamed tissues, they adapt to hypoxia and oxidative stress conditions, and to a reduction in nutrients. We aimed to investigate how this distinct environment regulates T cell responses within the inflamed joints of patients with childhood rheumatism (JIA) by analyzing the behavior of NRF2—the key regulator of the anti-oxidative stress response—and its signaling pathways. Methods: Flow cytometry and quantitative RT-PCR were used to perform metabolic profiling of T cells and to measure the production of inflammatory cytokines. Loss of function analyses were carried out by means of siRNA transfection experiments. NRF2 activation was induced by treatment with 4-octyl-Itaconate (4-OI). Results: Flow cytometry analyses revealed a high metabolic status in CD4+ T cells taken from synovial fluid (SF) with greater mitochondrial mass, and increased glucose and fatty acid uptake. This resulted in a heightened oxidative status of SF CD4+ T cells. Despite raised ROS levels, expression of NRF2 and its target gene NQO1 were lower in CD4+ T cells from SF than in those from blood. Indeed, NRF2 activation of CD4+ T cells downregulated oxidative stress markers, altered the metabolic phenotype and reduced secretion of IFN-γ. Conclusion: NRF2 could be a potential regulator in CD4+ T cells during chronic inflammation and could instigate a drift toward disease progression or regression, depending on the inflammatory environment. MDPI 2022-12-08 /pmc/articles/PMC9774972/ /pubmed/36552634 http://dx.doi.org/10.3390/antiox11122426 Text en © 2022 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 Rajendiran, Anandhi Subramanyam, Sudheendra Hebbar Klemm, Patricia Jankowski, Vera van Loosdregt, Jorg Vastert, Bas Vollbach, Kristina Wagner, Norbert Tenbrock, Klaus Ohl, Kim NRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA |
title | NRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA |
title_full | NRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA |
title_fullStr | NRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA |
title_full_unstemmed | NRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA |
title_short | NRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA |
title_sort | nrf2/itaconate axis regulates metabolism and inflammatory properties of t cells in children with jia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9774972/ https://www.ncbi.nlm.nih.gov/pubmed/36552634 http://dx.doi.org/10.3390/antiox11122426 |
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