Succinate mediates inflammation-induced adrenocortical dysfunction
- TU Dresden, Germany
- Vrije Universiteit, Netherlands
- Helmholtz Zentrum München, Germany
- University of Crete, Greece
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.
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Effect of LPS treatment on gene expression in the murine adrenal cortexNCBI Gene Expression Omnibus, GSE200220.
Article and author information
Author details
Vasileia Ismini Alexaki
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.
Ethics
Animal experimentation: The animal experiments were approved by the Landesdirektion Sachsen Germany (protocol number TVV57/2018).
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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