Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids

Jean-Philippe Auger, Max Zimmermann, Maria Faas, Ulrich Stifel, David Chambers, Brenda Krishnacoumar, R. Verena Taudte, Charlotte Grund, Gitta Erdmann, Carina Scholtysek, Stefan Uderhardt, Oumaima Ben Brahim, Mónica Pascual Maté, Cornelia Stoll, Martin Böttcher, Katrin Palumbo-Zerr, Matthew S. J. Mangan, Maria Dzamukova, Markus Kieler, Melanie Hofmann, Stephan Blüml, Gernot Schabbauer, Dimitrios Mougiakakos, Uwe Sonnewald, Fabian Hartmann, David Simon, Arnd Kleyer, Anika Grüneboom, Susetta Finotto, Eicke Latz, Jörg Hofmann, Georg Schett, Jan Tuckermann and Gerhard Krönke ()
Additional contact information
Jean-Philippe Auger: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Max Zimmermann: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Maria Faas: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Ulrich Stifel: Ulm University
David Chambers: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Brenda Krishnacoumar: Leibniz-Institut für Analytische Wissenschaften, ISAS, e.V
R. Verena Taudte: University of Erlangen-Nuremberg
Charlotte Grund: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Gitta Erdmann: German Cancer Research Centre (DKFZ)
Carina Scholtysek: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Stefan Uderhardt: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Oumaima Ben Brahim: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Mónica Pascual Maté: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Cornelia Stoll: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Martin Böttcher: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Katrin Palumbo-Zerr: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Matthew S. J. Mangan: University of Bonn
Maria Dzamukova: Charité - Universitätsmedizin Berlin
Markus Kieler: Medical University Vienna
Melanie Hofmann: Medical University Vienna
Stephan Blüml: Medical University of Vienna
Gernot Schabbauer: Medical University Vienna
Dimitrios Mougiakakos: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Uwe Sonnewald: University of Erlangen-Nuremberg
Fabian Hartmann: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
David Simon: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Arnd Kleyer: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Anika Grüneboom: Leibniz-Institut für Analytische Wissenschaften, ISAS, e.V
Susetta Finotto: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Eicke Latz: University of Bonn
Jörg Hofmann: University of Erlangen-Nuremberg
Georg Schett: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen
Jan Tuckermann: Ulm University
Gerhard Krönke: University of Erlangen-Nuremberg and Universitätsklinikum Erlangen

Nature, 2024, vol. 629, issue 8010, 184-192

Abstract: Abstract Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood1. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex whereby glucocorticoids provoke an increase in activity and enable an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA-cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. By contrast, artificial blocking of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, interferes with the anti-inflammatory effects of glucocorticoids and, accordingly, abrogates their beneficial effects during a diverse range of preclinical models of immune-mediated inflammatory diseases. Our findings provide important insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs.

Date: 2024
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DOI: 10.1038/s41586-024-07282-7

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