Lactate induces metabolic and epigenetic reprogramming of pro‐inflammatory Th17 cells

Report10 October 2022 Source DataTransparent process Lactate induces metabolic and epigenetic reprogramming of pro-inflammatory Th17 cells Aleksandra Lopez Krol Aleksandra Lopez Krol Institute for Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany Contribution: Conceptualization, Software, Formal analysis, Supervision, ​Investigation, Methodology, Writing - original draft, Writing - review & editing Search for more papers by this author Hannah P Nehring Hannah P Nehring orcid.org/0000-0002-7964-2107 Institute for Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany Contribution: ​Investigation, Methodology Search for more papers by this author Felix F Krause Felix F Krause Institute for Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany Contribution: ​Investigation, Methodology Search for more papers by this author Anne Wempe Anne Wempe Institute for Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany Contribution: ​Investigation, Methodology Search for more papers by this author Hartmann Raifer Hartmann Raifer Flow Cytometry Core Facility, Philipps-University, Marburg, Germany Contribution: Data curation, Software, ​Investigation, Methodology Search for more papers by this author Andrea Nist Andrea Nist Genomics Core Facility, Philipps-University, Marburg, Germany Contribution: Resources, Data curation, Software, Formal analysis, ​Investigation, Methodology Search for more papers by this author Thorsten Stiewe Thorsten Stiewe orcid.org/0000-0003-0134-7826 Genomics Core Facility, Philipps-University, Marburg, Germany Institute of Molecular Oncology, Philipps-University, Marburg, Germany German Center for Lung Research (DZL), Philipps-University, Marburg, Germany Contribution: Resources, Data curation, Software, Validation, ​Investigation, Methodology Search for more papers by this author Wilhelm Bertrams Wilhelm Bertrams orcid.org/0000-0002-2767-3606 German Center for Lung Research (DZL), Philipps-University, Marburg, Germany Institute for Lung Research, UGMLC, Philipps-University, Marburg, Germany Contribution: Resources, Data curation, Software, Validation, ​Investigation, Visualization Search for more papers by this author Bernd Schmeck Bernd Schmeck German Center for Lung Research (DZL), Philipps-University, Marburg, Germany Institute for Lung Research, UGMLC, Philipps-University, Marburg, Germany Contribution: Resources, Software, Supervision, Validation, Methodology Search for more papers by this author Maik Luu Maik Luu Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany Contribution: ​Investigation, Methodology Search for more papers by this author Hanna Leister Hanna Leister Institute for Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany Contribution: Data curation, Software, Supervision, ​Investigation, Methodology Search for more papers by this author Ho-Ryun Chung Ho-Ryun Chung Institute for Medical Bioinformatics and Biostatistics, Philipps-University, Marburg, Germany Contribution: Resources, Data curation, Software, Supervision, Validation, Visualization, Methodology Search for more papers by this author Uta-Maria Bauer Uta-Maria Bauer orcid.org/0000-0003-1344-9117 Institute for Medical Bioinformatics and Biostatistics, Philipps-University, Marburg, Germany Contribution: Resources, Data curation, Formal analysis, Supervision, Validation, Methodology Search for more papers by this author Till Adhikary Till Adhikary Institute for Medical Bioinformatics and Biostatistics, Philipps-University, Marburg, Germany Institute for Molecular Biology and Tumor Research (IMT), Philipps-University, Marburg, Germany Contribution: Resources, Data curation, Software, Supervision, ​Investigation, Methodology, Writing - original draft Search for more papers by this author Alexander Visekruna Corresponding Author Alexander Visekruna [email protected] orcid.org/0000-0002-5207-9545 Institute for Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany Contribution: Conceptualization, Data curation, Supervision, Funding acquisition, Writing - original draft, Writing - review & editing Search for more papers by this author Aleksandra Lopez Krol Aleksandra Lopez Krol Institute for Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany Contribution: Conceptualization, Software, Formal analysis, Supervision, ​Investigation, Methodology, Writing - original draft, Writing - review & editing Search for more papers by this author Hannah P Nehring Hannah P Nehring orcid.org/0000-0002-7964-2107 Institute for Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany Contribution: ​Investigation, Methodology Search for more papers by this author Felix F Krause Felix F Krause Institute for Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany Contribution: ​Investigation, Methodology Search for more papers by this author Anne Wempe Anne Wempe Institute for Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany Contribution: ​Investigation, Methodology Search for more papers by this author Hartmann Raifer Hartmann Raifer Flow Cytometry Core Facility, Philipps-University, Marburg, Germany Contribution: Data curation, Software, ​Investigation, Methodology Search for more papers by this author Andrea Nist Andrea Nist Genomics Core Facility, Philipps-University, Marburg, Germany Contribution: Resources, Data curation, Software, Formal analysis, ​Investigation, Methodology Search for more papers by this author Thorsten Stiewe Thorsten Stiewe orcid.org/0000-0003-0134-7826 Genomics Core Facility, Philipps-University, Marburg, Germany Institute of Molecular Oncology, Philipps-University, Marburg, Germany German Center for Lung Research (DZL), Philipps-University, Marburg, Germany Contribution: Resources, Data curation, Software, Validation, ​Investigation, Methodology Search for more papers by this author Wilhelm Bertrams Wilhelm Bertrams orcid.org/0000-0002-2767-3606 German Center for Lung Research (DZL), Philipps-University, Marburg, Germany Institute for Lung Research, UGMLC, Philipps-University, Marburg, Germany Contribution: Resources, Data curation, Software, Validation, ​Investigation, Visualization Search for more papers by this author Bernd Schmeck Bernd Schmeck German Center for Lung Research (DZL), Philipps-University, Marburg, Germany Institute for Lung Research, UGMLC, Philipps-University, Marburg, Germany Contribution: Resources, Software, Supervision, Validation, Methodology Search for more papers by this author Maik Luu Maik Luu Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany Contribution: ​Investigation, Methodology Search for more papers by this author Hanna Leister Hanna Leister Institute for Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany Contribution: Data curation, Software, Supervision, ​Investigation, Methodology Search for more papers by this author Ho-Ryun Chung Ho-Ryun Chung Institute for Medical Bioinformatics and Biostatistics, Philipps-University, Marburg, Germany Contribution: Resources, Data curation, Software, Supervision, Validation, Visualization, Methodology Search for more papers by this author Uta-Maria Bauer Uta-Maria Bauer orcid.org/0000-0003-1344-9117 Institute for Medical Bioinformatics and Biostatistics, Philipps-University, Marburg, Germany Contribution: Resources, Data curation, Formal analysis, Supervision, Validation, Methodology Search for more papers by this author Till Adhikary Till Adhikary Institute for Medical Bioinformatics and Biostatistics, Philipps-University, Marburg, Germany Institute for Molecular Biology and Tumor Research (IMT), Philipps-University, Marburg, Germany Contribution: Resources, Data curation, Software, Supervision, ​Investigation, Methodology, Writing - original draft Search for more papers by this author Alexander Visekruna Corresponding Author Alexander Visekruna [email protected] orcid.org/0000-0002-5207-9545 Institute for Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany Contribution: Conceptualization, Data curation, Supervision, Funding acquisition, Writing - original draft, Writing - review & editing Search for more papers by this author Author Information Aleksandra Lopez Krol1, Hannah P Nehring1, Felix F Krause1, Anne Wempe1, Hartmann Raifer2, Andrea Nist3, Thorsten Stiewe3,4,5, Wilhelm Bertrams5,6, Bernd Schmeck5,6, Maik Luu7, Hanna Leister1, Ho-Ryun Chung8, Uta-Maria Bauer8, Till Adhikary8,9 and Alexander Visekruna *,1 1Institute for Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany 2Flow Cytometry Core Facility, Philipps-University, Marburg, Germany 3Genomics Core Facility, Philipps-University, Marburg, Germany 4Institute of Molecular Oncology, Philipps-University, Marburg, Germany 5German Center for Lung Research (DZL), Philipps-University, Marburg, Germany 6Institute for Lung Research, UGMLC, Philipps-University, Marburg, Germany 7Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany 8Institute for Medical Bioinformatics and Biostatistics, Philipps-University, Marburg, Germany 9Institute for Molecular Biology and Tumor Research (IMT), Philipps-University, Marburg, Germany *Corresponding author. Tel: +49 64212864359; E-mail: [email protected] EMBO Reports (2022)23:e54685https://doi.org/10.15252/embr.202254685 Full textView the full text of the articlePDFDownload PDF of article text and main figures.PDF PLUSDownload PDF of article text, main figures, expanded view figures and appendix. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Increased lactate levels in the tissue microenvironment are a well-known feature of chronic inflammation. However, the role of lactate in regulating T cell function remains controversial. Here, we demonstrate that extracellular lactate predominantly induces deregulation of the Th17-specific gene expression program by modulating the metabolic and epigenetic status of Th17 cells. Following lactate treatment, Th17 cells significantly reduced their IL-17A production and upregulated Foxp3 expression through ROS-driven IL-2 secretion. Moreover, we observed increased levels of genome-wide histone H3K18 lactylation, a recently described marker for active chromatin in macrophages, in lactate-treated Th17 cells. In addition, we show that high lactate concentrations suppress Th17 pathogenicity during intestinal inflammation in mice. These results indicate that lactate is capable of reprogramming pro-inflammatory T cell phenotypes into regulatory T cells. Synopsis Lactate is a common metabolite in the tumor and inflammatory environment. High extracellular lactate concentrations promote the reprogramming of pro-inflammatory Th17 cells towards regulatory T cell-like phenotypes by metabolic and epigenetic mechanisms. Lactate, a co-product of glycolysis, increases mitochondrial oxidative phosphorylation and ROS production in Th17 cells. ROS-dependent IL-2 signaling induces Foxp3 expression and suppresses the production of IL-17A. Treatment of Th17 cells with extracellular lactate leads to an enrichment of H3K18 lactylation at the Foxp3 locus. Lactate promotes phenotypic switching of Th17 effector cells to regulatory T cells. Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 23,Issue 12,06 December 2022This month's cover highlights the article Cryo–EM structure of the octameric pore of Clostridium perfringens β–toxin by Julia Bruggisser, Ioan Iacovache, Horst Posthaus, Benoît Zuber and colleagues. The cover shows two octameric pores of C. Perfringens β–toxin in a lipid bilayer. One pore is shown bound to its receptor CD31 while the second is shown as cut through at the edge of the membrane. Alternating protomers in the oligomer are shown in different shades of blue while for the receptor, which was model based on an AlphaFold prediction, alternating Ig domains are shown in different shades of yellow. (Scientific image by Ioan Iacovache and Julia Bruggisser. Illustration created in Blender (http://www.blender.org) using a phospholipid bilayer template by Dr. Joseph G. Manion (https://cgfigures.gumroad.com/l/eJzxj. Copyright (author or institute): Institute of Anatomy, University of Bern) Volume 23Issue 126 December 2022In this issue RelatedDetailsLoading ...