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Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids
Nature (London), 2024-05, Vol.629 (8010), p.184-192
2024
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Autor(en) / Beteiligte
Titel
Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids
Ist Teil von
  • Nature (London), 2024-05, Vol.629 (8010), p.184-192
Ort / Verlag
England: Nature Publishing Group
Erscheinungsjahr
2024
Quelle
MEDLINE
Beschreibungen/Notizen
  • 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.
Sprache
Englisch
Identifikatoren
ISSN: 0028-0836, 1476-4687
eISSN: 1476-4687
DOI: 10.1038/s41586-024-07282-7
Titel-ID: cdi_swepub_primary_oai_prod_swepub_kib_ki_se_155786454
Format
–
Schlagworte
Aconitate decarboxylase, Animals, Anti-inflammatory agents, Anti-Inflammatory Agents - pharmacology, Carbon, Carboxy-Lyases - antagonists & inhibitors, Carboxy-Lyases - metabolism, Citric Acid Cycle - drug effects, Citric Acid Cycle - genetics, Cytokines - immunology, Cytokines - metabolism, Dehydrogenases, Drug development, Enzyme Activation - drug effects, Female, Glucocorticoid receptors, Glucocorticoids, Glucocorticoids - metabolism, Glucocorticoids - pharmacology, Glucose, Humans, Hydro-Lyases - deficiency, Hydro-Lyases - genetics, Immune system, Immunosuppressive agents, Inflammation - drug therapy, Inflammation - metabolism, Inflammatory diseases, Inflammatory response, Macrophages, Macrophages - cytology, Macrophages - drug effects, Macrophages - immunology, Macrophages - metabolism, Male, Medicin och hälsovetenskap, Metabolism, Metabolites, Mice, Mice, Inbred C57BL, Mitochondria, Mitochondria - drug effects, Mitochondria - metabolism, Mode of action, Molecular modelling, Pyruvate dehydrogenase (lipoamide), Pyruvate Dehydrogenase Complex - metabolism, Pyruvic acid, Receptors, Glucocorticoid - metabolism, Respiration, Succinates - metabolism, Transcription factors, Tricarboxylic acid cycle

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