ESPEYB21 14. The Year in Science and Medicine Risk and Outcome (5 abstracts)
14.14. 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 & Gerhard Krönke
Nature 2024 May;629(8010):184–192. doi: 10.1038/s41586-024-07282-7
Brief Summary:This study uncovers a novel mechanism for the anti-inflammatory effects of glucocorticoids (GCs) that involves reprogramming of mitochondrial metabolism in macrophages through enhanced production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. GCs have very potent anti-inflammatory properties, but the mechanisms are incompletely understood. GCs also have severe side effects when used in high doses for long-term, and therefore novel drugs are needed that ideally have the positive but not the negative properties of GCs.
This study used different approaches (macrophage cultures, ex vivo human biomaterials and inflammatory mice models) to study the exact mechanism of GCs’ effect in macrophages. Selected main findings in brief: GC treatment of LPS-activated, inflammatory ‘hot’ macrophages provoked a global increase in mitochondrial pyruvate consumption by increasing the enzymatic activity of mitochondrial pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) enzymes stimulating the tricarboxylic acid (TCA; Krebs) cycle in mitochondria. This mitochondrial stimulation resulted in increased production of itaconate, a potent anti-inflammatory molecule that interferes with the transcription of pro-inflammatory genes. Production of itaconate depends on the enzyme aconitate decarboxylase (ACOD1) and its gene expression was significantly altered in LPS-induced macrophages.
In line with findings in macrophages, GCs had a reduced effect on inflammatory cytokines in Acod1−/− mice, but the effect could be rescued by itaconate mimetics. Higher itaconate serum levels were found in GC treated patients with rheumatoid arthritis.
Taken together, the anti-inflammatory effects of GCs in different immune-mediated inflammatory diseases (e.g., rheumatoid arthritis or asthma) depend on GC-induced mitochondrial reprogramming. This understanding might provide targets for novel drugs to deliver the anti-inflammatory effects of GCs without their side effects.
Volume 21
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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