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, Pascual Maté Mónica, Stoll Cornelia, Böttcher Martin, Palumbo-Zerr Katrin, Mangan Matthew S J, Dzamukova Maria, Kieler Markus, Hofmann Melanie, Blüml Stephan, Schabbauer Gernot, Mougiakakos Dimitrios, Sonnewald Uwe, Hartmann Fabian, Simon David, Kleyer Arnd, Grüneboom Anika, Finotto Susetta, Latz Eicke, Hofmann Jörg, Schett Georg, Tuckermann Jan, Krönke Gerhard
Department of Internal Medicine 3, University of Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany.
Deutsches Zentrum für Immuntherapie (DZI), University of Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany.
Nature. 2024 May;629(8010):184-192. doi: 10.1038/s41586-024-07282-7. Epub 2024 Apr 10.
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.
糖皮质激素是治疗多种免疫介导的炎症性疾病的主要药物。然而，其抗炎作用的分子机制仍未完全明确。在此，我们表明糖皮质激素的抗炎特性涉及巨噬细胞线粒体代谢的重编程，导致抗炎代谢物衣康酸的产生增加并持续，从而抑制炎症反应。糖皮质激素受体与丙酮酸脱氢酶复合体的部分相互作用，由此糖皮质激素促使活性增加，并使原本促炎的巨噬细胞中三羧酸（TCA）循环加速且出现反常通量。这种糖皮质激素介导的线粒体代谢重排增强了整个炎症反应过程中TCA循环依赖性的衣康酸产生，从而干扰促炎细胞因子的产生。相比之下，人为阻断TCA循环或衣康酸合成的限速酶乌头酸脱羧酶1基因缺陷，会干扰糖皮质激素的抗炎作用，因此在多种免疫介导的炎症性疾病临床前模型中消除了它们的有益作用。我们的研究结果为糖皮质激素抗炎特性提供了重要见解，并对新型抗炎药物的设计具有重大意义。
