POS0460 METABOLIC REWIRING PROMOTES ANTI-INFLAMMATORY EFFECTS OF GLUCOCORTICOIDS
Authors: J. P. Auger, M. Zimmermann, M. Faas, U. Stifel, D. Chambers, B. Krishnacoumar, R. V. Taudte, C. Grund, C. Scholtysek, S. Uderhardt, M. Pascual Maté, C. Stoll, M. Böttcher, K. Palumbo-Zerr, M. Mangan, M. Dzamukova, M. Kieler, M. Hofmann, S. Blüml, G. Schabbauer, D. Mougiakakos, U. Sonnewald, F. Hartmann, D. Simon, A. Kleyer, A. Grüneboom, S. Finotto, E. Latz, J. Hofmann, G. Schett, J. Tuckermann, G. Krönke
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Glucocorticoids (GCs) represent the most potent class of anti-inflammatory drugs and are an essential component of the therapy of various immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis. A major drawback of GC-based treatment regimens are severe side effects, a circumstance that limits their long-term use and highlights the need for a better understanding of their molecular mode of action. Binding of GCs to the cytoplasmic GC receptor (GR) results in its nuclear translocation and binding to specific responsive elements where the GR acts as ligand-activated transcription factor and actively drives the expression of its target genes. Such a GR-mediated transcriptional "transactivation", however, does not account for the full spectrum of anti-inflammatory effects exerted by GCs in cells of the innate immune system. As such, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood. <h3>Objectives:</h3> In this study, we aim to determine the contribution of genomic and non-genomic mechanisms to the anti-inflammatory effects of GCs in innate immune cells. This work will contribute to our knowledge of the beneficial effects of GCs and provide avenues to specifically target these mechanisms. <h3>Methods:</h3> Bulk RNA sequencing and metabolomic analyses of <i>in vitro</i>-cultured pro-inflammatory murine macrophages allowed us to better dissect the contribution of the mechanisms of action of the GR to the anti-inflammatory effects of GCs. These results were then validated in <i>in vitro</i>-cultured pro-inflammatory human macrophages. Various <i>in vivo</i> mouse models of inflammation (acute lung injury, ovalbumin-induced asthma and K/BxN serum transfer arthritis) were utilized alongside the evaluation in serum from patients with rheumatoid arthritis treated with or without GCs. <h3>Results:</h3> We showed that the anti-inflammatory properties of GCs involve a reprogramming of the mitochondrial metabolism of macrophages, which results in an increased and sustained production of the anti-inflammatory metabolite itaconate and a consequent inhibition of the inflammatory response. The GR interacts with parts of the pyruvate dehydrogenase complex where GCs provoke an increase in activity and allow an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This GC-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. Artificial block of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, in contrast, interferes with the anti-inflammatory effects of GCs and accordingly abrogates their beneficial effects during a diverse range of preclinical models of IMIDs. <h3>Conclusion:</h3> Our findings provide important additional insights into the anti-inflammatory properties of GCs and have substantial implications for the future design of novel classes of anti-inflammatory drugs. <h3>Acknowledgements:</h3> We thank W. Baum who helped generating the K/BxN serum as well as A. Klej, R. Weinkam and R. Mancuso for excellent technical assistance. <h3>REFERENCES: NIL.</h3> <h3>Disclosure of Interests:</h3> <b>None declared.</b>