德国埃尔朗根-纽伦堡大学Gerhard Krönke研究组发现，代谢重塑促进糖皮质激素的抗炎作用。2024年4月10日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员发现糖皮质激素的抗炎特性涉及对巨噬细胞线粒体新陈代谢的重编程，从而导致抗炎代谢物衣康酸的持续产生，并由此抑制炎症反应。糖皮质激素受体与丙酮酸脱氢酶复合物的某些部分相互作用，从而使糖皮质激素的活性增加，并使原本具有促炎作用的巨噬细胞的三羧酸（TCA）循环加速和自相矛盾地流动。

这种由糖皮质激素介导的线粒体新陈代谢重新布线，会在整个炎症反应过程中增强依赖TCA循环产生的衣康酸，从而干扰促炎细胞因子的产生。与此相反，人为阻断TCA循环或缺乏丙酮酸脱羧酶1（衣康酸合成的限速酶）会干扰糖皮质激素的抗炎作用，从而在各种免疫介导的炎症疾病临床前模型中削弱其有益作用。这些发现为了解糖皮质激素的抗炎特性提供了重要启示，对设计新型抗炎药物具有重大意义。

据悉，糖皮质激素是治疗各种免疫介导的炎症性疾病的主要药物。然而，人们对其抗炎作用模式的分子机制仍不甚了解。

附：英文原文

Title: Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids

Author: 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 Mat, Mnica, Stoll, Cornelia, Bttcher, Martin, Palumbo-Zerr, Katrin, Mangan, Matthew S. J., Dzamukova, Maria, Kieler, Markus, Hofmann, Melanie, Blml, Stephan, Schabbauer, Gernot, Mougiakakos, Dimitrios, Sonnewald, Uwe, Hartmann, Fabian, Simon, David, Kleyer, Arnd, Grneboom, Anika, Finotto, Susetta, Latz, Eicke, Hofmann, Jrg, Schett, Georg, Tuckermann, Jan, Krnke, Gerhard

Issue&Volume: 2024-04-10

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.

DOI: 10.1038/s41586-024-07282-7

Source: https://www.nature.com/articles/s41586-024-07282-7