Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids

• 成果类型: Article
• 署名作者: Auger, Jean-Philippe; Zimmermann, Max; Faas, Maria; Stifel, Ulrich; Chambers, David; Krishnacoumar, Brenda; Taudte, R. Verena; Grund, Charlotte; Erdmann, Gitta; Scholtysek, Carina; Uderhardt, Stefan; Ben Brahim, Oumaima; Mate, Monica Pascual; Stoll, Cornelia; Boettcher, Martin; Palumbo-Zerr, Katrin; Mangan, Matthew S. J.; Dzamukova, Maria; Kieler, Markus; Hofmann, Melanie; Blueml, Stephan; Schabbauer, Gernot; Mougiakakos, Dimitrios; Sonnewald, Uwe; Hartmann, Fabian; Simon, David; Kleyer, Arnd; Grueneboom, Anika; Finotto, Susetta; Latz, Eicke; Hofmann, Joerg; Schett, Georg; Tuckermann, Jan; Kroenke, Gerhard
• 署名单位: University of Erlangen Nuremberg; University of Erlangen Nuremberg; University of Erlangen Nuremberg; Ulm University; Dortmund University of Technology; Leibniz Association; Leibniz Institut fur Analytische Wissenschaften (ISAS); University of Duisburg Essen; University of Erlangen Nuremberg; Philipps University Marburg; Helmholtz Association; German Cancer Research Center (DKFZ); University of Erlangen Nuremberg; Otto von Guericke University; University of Bonn; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Medical University of Vienna; Medical University of Vienna; University of Erlangen Nuremberg; University of Erlangen Nuremberg; Leibniz Association; Deutsches Rheuma-Forschungszentrum (DRFZ)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6741
• DOI: 10.1038/s41586-024-07282-7
• 发表日期: 2024-05-02
• 页码: 184-+
• 关键词: itaconate; pyruvate; transrepression; gluconeogenesis; dehydrogenase; dexamethasone; inflammation; stimulation; receptor

摘要

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(1). 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 antiinflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs.