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Increased stromal PFKFB3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation

Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the intestinal tract with currently not well-understood pathogenesis. In addition to the involvement of immune cells, increasing studies show an important role for fibroblasts in the pathogenesis of IBD. Previous work showed tha...

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Autores principales: Zhou, Zhou, Plug, Leonie G., Patente, Thiago A., de Jonge-Muller, Eveline S. M., Elmagd, Amir Abou, van der Meulen-de Jong, Andrea E., Everts, Bart, Barnhoorn, Marieke C., Hawinkels, Lukas J. A. C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9670190/
https://www.ncbi.nlm.nih.gov/pubmed/36405760
http://dx.doi.org/10.3389/fimmu.2022.966067
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author Zhou, Zhou
Plug, Leonie G.
Patente, Thiago A.
de Jonge-Muller, Eveline S. M.
Elmagd, Amir Abou
van der Meulen-de Jong, Andrea E.
Everts, Bart
Barnhoorn, Marieke C.
Hawinkels, Lukas J. A. C.
author_facet Zhou, Zhou
Plug, Leonie G.
Patente, Thiago A.
de Jonge-Muller, Eveline S. M.
Elmagd, Amir Abou
van der Meulen-de Jong, Andrea E.
Everts, Bart
Barnhoorn, Marieke C.
Hawinkels, Lukas J. A. C.
author_sort Zhou, Zhou
collection PubMed
description Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the intestinal tract with currently not well-understood pathogenesis. In addition to the involvement of immune cells, increasing studies show an important role for fibroblasts in the pathogenesis of IBD. Previous work showed that glycolysis is the preferred energy source for fibroblasts in fibrotic diseases. 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) is a key kinase supporting glycolysis. Increased expression of PFKFB3 in several cancers and inflammatory diseases has been previously reported, but the metabolic status of fibroblasts and the role of PFKFB3 in patients with IBD are currently unknown. Therefore, in this study, we evaluated the role of glycolysis and PFKFB3 expression in IBD. Single-sample gene set enrichment analysis (ssGSEA) revealed that glycolysis was significantly higher in IBD intestinal samples, compared to healthy controls, which was confirmed in the validation cohorts of IBD patients. Single-cell sequencing data indicated that PFKFB3 expression was higher in IBD-derived stromal cells. In vitro, PFKFB3 expression in IBD-derived fibroblasts was increased after the stimulation with pro-inflammatory cytokines. Using seahorse real-time cell metabolic analysis, inflamed fibroblasts were shown to have a higher extracellular acidification rate and a lower oxygen consumption rate, which could be reversed by inhibition of JAK/STAT pathway. Furthermore, increased expression of pro-inflammatory cytokines and chemokines in fibroblasts could be reverted by PFK15, a specific inhibitor of PFKFB3. In vivo experiments showed that PFK15 reduced the severity of dextran sulfate sodium (DSS)- and Tcell transfer induced colitis, which was accompanied by a reduction in immune cell infiltration in the intestines. These findings suggest that increased stromal PFKFB3 expression contributes to inflammation and the pathological function of fibroblasts in IBD. Inhibition of PFKFB3 suppressed their inflammatory characteristics.
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spelling pubmed-96701902022-11-18 Increased stromal PFKFB3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation Zhou, Zhou Plug, Leonie G. Patente, Thiago A. de Jonge-Muller, Eveline S. M. Elmagd, Amir Abou van der Meulen-de Jong, Andrea E. Everts, Bart Barnhoorn, Marieke C. Hawinkels, Lukas J. A. C. Front Immunol Immunology Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the intestinal tract with currently not well-understood pathogenesis. In addition to the involvement of immune cells, increasing studies show an important role for fibroblasts in the pathogenesis of IBD. Previous work showed that glycolysis is the preferred energy source for fibroblasts in fibrotic diseases. 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) is a key kinase supporting glycolysis. Increased expression of PFKFB3 in several cancers and inflammatory diseases has been previously reported, but the metabolic status of fibroblasts and the role of PFKFB3 in patients with IBD are currently unknown. Therefore, in this study, we evaluated the role of glycolysis and PFKFB3 expression in IBD. Single-sample gene set enrichment analysis (ssGSEA) revealed that glycolysis was significantly higher in IBD intestinal samples, compared to healthy controls, which was confirmed in the validation cohorts of IBD patients. Single-cell sequencing data indicated that PFKFB3 expression was higher in IBD-derived stromal cells. In vitro, PFKFB3 expression in IBD-derived fibroblasts was increased after the stimulation with pro-inflammatory cytokines. Using seahorse real-time cell metabolic analysis, inflamed fibroblasts were shown to have a higher extracellular acidification rate and a lower oxygen consumption rate, which could be reversed by inhibition of JAK/STAT pathway. Furthermore, increased expression of pro-inflammatory cytokines and chemokines in fibroblasts could be reverted by PFK15, a specific inhibitor of PFKFB3. In vivo experiments showed that PFK15 reduced the severity of dextran sulfate sodium (DSS)- and Tcell transfer induced colitis, which was accompanied by a reduction in immune cell infiltration in the intestines. These findings suggest that increased stromal PFKFB3 expression contributes to inflammation and the pathological function of fibroblasts in IBD. Inhibition of PFKFB3 suppressed their inflammatory characteristics. Frontiers Media S.A. 2022-11-02 /pmc/articles/PMC9670190/ /pubmed/36405760 http://dx.doi.org/10.3389/fimmu.2022.966067 Text en Copyright © 2022 Zhou, Plug, Patente, de Jonge-Muller, Elmagd, van der Meulen-de Jong, Everts, Barnhoorn and Hawinkels https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Zhou, Zhou
Plug, Leonie G.
Patente, Thiago A.
de Jonge-Muller, Eveline S. M.
Elmagd, Amir Abou
van der Meulen-de Jong, Andrea E.
Everts, Bart
Barnhoorn, Marieke C.
Hawinkels, Lukas J. A. C.
Increased stromal PFKFB3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation
title Increased stromal PFKFB3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation
title_full Increased stromal PFKFB3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation
title_fullStr Increased stromal PFKFB3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation
title_full_unstemmed Increased stromal PFKFB3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation
title_short Increased stromal PFKFB3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation
title_sort increased stromal pfkfb3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9670190/
https://www.ncbi.nlm.nih.gov/pubmed/36405760
http://dx.doi.org/10.3389/fimmu.2022.966067
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