Center of Neurogenomics and Cognitive Research (CNCR), Department of Molecular and 10 Cellular Neurobiology, Vrije Universiteit, Amsterdam, Netherlands
Na Sun
Research Unit Analytical Pathology, German Research Center for Environmental Health, Helmholtz Zentrum München, Munich, Germany
Ourania Kolliniati
Department of Clinical Chemistry, Medical School, University of Crete, Heraklion, Greece
Maria Patschin
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital, Technische Universität Dresden, Dresden, Germany
Heba Abdelmegeed
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital, Technische Universität Dresden, Dresden, Germany
Holger Henneicke
Department of Medicine III & Center for Healthy Ageing, Technische Universität Dresden, Dresden, Germany; Center for Regenerative Therapies, TU Dresden, Technische Universität Dresden, Dresden, Germany
Waldemar Kanczkowski
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital, Technische Universität Dresden, Dresden, Germany
Ben Wielockx
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital, Technische Universität Dresden, Dresden, Germany
Christos Tsatsanis
Department of Clinical Chemistry, Medical School, University of Crete, Heraklion, Greece
Center of Neurogenomics and Cognitive Research (CNCR), Department of Molecular and 10 Cellular Neurobiology, Vrije Universiteit, Amsterdam, Netherlands
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 adrenal dysfunction in severe inflammation, but also offer a potential target for therapeutic intervention.
