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Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids.


Authors: 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, Gerhard Krönke

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 understood. 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.

© 2024. The Author(s), under exclusive licence to Springer Nature Limited.

PMID: 38600378

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