Abstract

The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of anti-inflammatory glucocorticoids by the adrenal cortex, thereby representing an endogenous feedback loop. However, severe inflammation reduces the responsiveness of the adrenal gland to adrenocorticotropic hormone (ACTH), although the underlying mechanisms are poorly understood. Here, we show by transcriptomic, proteomic and metabolomic analyses that LPS-induced systemic inflammation triggers profound metabolic changes in steroidogenic adrenocortical cells, including downregulation of the TCA cycle and oxidative phosphorylation, in mice. Inflammation disrupts the TCA cycle at the level of succinate dehydrogenase (SDH), leading to succinate accumulation and disturbed steroidogenesis. Mechanistically, IL-1β reduces SDHB expression through upregulation of DNA methyltransferase 1 (DNMT1) and methylation of the SDHB promoter. Consequently, increased succinate levels impair oxidative phosphorylation and ATP synthesis and enhance ROS production, leading to reduced steroidogenesis. Together, we demonstrate that the IL-1β-DNMT1-SDHB-succinate axis disrupts steroidogenesis. Our findings not only provide a mechanistic explanation for the adrenal dysfunction in severe inflammation, but also offer a potential target for therapeutic intervention.

Data availability

RNA-Seq data are available in: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE200220.The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository, with the dataset identifier PXD036542. Once the article is accepted, data will be made public and accessible.

The following data sets were generated

Article and author information

Author details

  1. Ivona Mateska

    Institute of Clinical Chemistry and Laboratory Medicine, TU Dresden, Dresden, Germany
    For correspondence
    Ivona.Mateska@uniklinikum-dresden.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6150-9175
  2. Anke Witt

    Institute of Clinical Chemistry and Laboratory Medicine, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Eman Hagag

    Institute of Clinical Chemistry and Laboratory Medicine, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Anupam Sinha

    Institute of Clinical Chemistry and Laboratory Medicine, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Canelif Yilmaz

    Institute of Clinical Chemistry and Laboratory Medicine, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9676-9310
  6. Evangelia Thanou

    Department of Molecular and Cellular Neurobiology, Vrije Universiteit, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6843-4591
  7. Na Sun

    Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Ourania Kolliniati

    Department of Clinical Chemistry, University of Crete, Heraklion, Greece
    Competing interests
    The authors declare that no competing interests exist.
  9. Maria Patschin

    Institute for Clinical Chemistry and Laboratory Medicine, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Heba Abdelmegeed

    Institute for Clinical Chemistry and Laboratory Medicine, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Holger Henneicke

    enter for Regenerative Therapies, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Waldemar Kanczkowski

    Institute for Clinical Chemistry and Laboratory Medicine, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Ben Wielockx

    Institute for Clinical Chemistry and Laboratory Medicine, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Christos Tsatsanis

    Department of Clinical Chemistry, University of Crete, Heraklion, Greece
    Competing interests
    The authors declare that no competing interests exist.
  15. Andreas Dahl

    Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2668-8371
  16. Axel Karl Walch

    Research Unit Analytical Pathology, Helmholtz Zentrum München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  17. Ka Wan Li

    Center of Neurogenomics and Cognitive Research, Vrije Universiteit, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6983-5055
  18. Mirko Peitzsch

    Institute of Clinical Chemistry and Laboratory Medicine, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2472-675X
  19. Triantafyllos Chavakis

    Institute of Clinical Chemistry and Laboratory Medicine, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  20. Vasileia Ismini Alexaki

    Institute of Clinical Chemistry and Laboratory Medicine, TU Dresden, Dresden, Germany
    For correspondence
    VasileiaIsmini.Alexaki@uniklinikum-dresden.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3935-8985

Funding

Deutsche Forschungsgemeinschaft (SFB/TRR205)

  • Ben Wielockx
  • Mirko Peitzsch
  • Vasileia Ismini Alexaki

HORIZON EUROPE Framework Programme (Marie Skłodowska-Curie grant agreement No 765704)

  • Vasileia Ismini Alexaki

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Thomas L Clemens, University of Maryland School of Medicine, United States

Ethics

Animal experimentation: The animal experiments were approved by the Landesdirektion Sachsen Germany (protocol number TVV57/2018).

Version history

  1. Preprint posted: May 1, 2022 (view preprint)
  2. Received: August 30, 2022
  3. Accepted: July 13, 2023
  4. Accepted Manuscript published: July 14, 2023 (version 1)
  5. Version of Record published: July 27, 2023 (version 2)

Copyright

© 2023, Mateska et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ivona Mateska
  2. Anke Witt
  3. Eman Hagag
  4. Anupam Sinha
  5. Canelif Yilmaz
  6. Evangelia Thanou
  7. Na Sun
  8. Ourania Kolliniati
  9. Maria Patschin
  10. Heba Abdelmegeed
  11. Holger Henneicke
  12. Waldemar Kanczkowski
  13. Ben Wielockx
  14. Christos Tsatsanis
  15. Andreas Dahl
  16. Axel Karl Walch
  17. Ka Wan Li
  18. Mirko Peitzsch
  19. Triantafyllos Chavakis
  20. Vasileia Ismini Alexaki
(2023)
Succinate mediates inflammation-induced adrenocortical dysfunction
eLife 12:e83064.
https://doi.org/10.7554/eLife.83064

Share this article

https://doi.org/10.7554/eLife.83064

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