TY - GEN A1 - Radushev, Veselina A1 - Karkossa, Isabel A1 - Berg, Janina A1 - Bergen, Martin von A1 - Engelmann, Beatrice A1 - Rolle-Kampczyk, Ulrike A1 - Blüher, Matthias A1 - Wagner, Ulf A1 - Schubert, Kristin A1 - Rossol, Manuela T1 - Dysregulated cytokine and oxidative response in hyper-glycolytic monocytes in obesity T2 - Frontiers in Immunology N2 - Introduction: Obesity is associated with a plethora of health complications, including increased susceptibility to infections or decreased vaccine efficacy, partly due to dysregulated immune responses. Monocytes play a crucial role in innate immunity, yet their functional alterations in obesity remain poorly understood. Methods: Here, we employed proteomic and metabolomic analyses to investigate monocyte characteristics in individuals with overweight, obesity, impaired glucose tolerance (IGT), and type 2 diabetes (T2D), compared to lean donors. Results and discussion: Our results revealed distinct molecular signatures in monocytes from individuals with obesity, with significant alterations in pathways related to metabolism, cellular migration, and phagocytosis. Moreover, LPS-induced activation of monocytes unveiled heightened metabolic reprogramming towards glycolysis in subjects with obesity accompanied by dysregulated cytokine responses and elevated oxidative stress. Additionally, monocytes from donors with obesity exhibited increased lipid droplet accumulation. These findings shed light on the immunometabolic dysregulation underlying obesity-associated immune dysfunction, highlighting potential targets for therapeutic intervention. KW - monocytes KW - immunometabolism KW - respiratory burst KW - obesity KW - IL-8 Y1 - 2024 U6 - https://doi.org/10.3389/fimmu.2024.1416543 SN - 1664-3224 VL - 15 PB - Frontiers Media S.A. ER - TY - JOUR A1 - Raulien, Nora A1 - Friedrich, Kathleen A1 - Strobel, Sarah A1 - Raps, Stefanie A1 - Hecker, Friederike A1 - Pierer, Matthias A1 - Schilling, Erik A1 - Lainka, Elke A1 - Kallinich, Tilmann A1 - Baumann, Sven A1 - Fritz-Wallace, Katarina A1 - Rolle-Kampczyk, Ulrike A1 - Bergen, Martin von A1 - Aigner, Achim A1 - Ewe, Alexander A1 - Schett, Georg A1 - Cross, Michael A1 - Rossol, Manuela A1 - Wagner, Ulf T1 - Glucose-oxygen deprivation constrains HMGCR function and Rac1 prenylation and activates the NLRP3 inflammasome in human monocytes JF - Science Signaling N2 - Hypoxia and low glucose abundance often occur simultaneously at sites of inflammation. In monocytes and macrophages, glucose-oxygen deprivation stimulates the assembly of the NLRP3 inflammasome to generate the proinflammatory cytokine IL-1β. We found that concomitant glucose deprivation and hypoxia activated the NLRP3 inflammasome by constraining the function of HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate kinase pathway. HMGCR is involved in the synthesis of geranylgeranyl pyrophosphate (GGPP), which is required for the prenylation and lipid membrane integration of proteins. Under glucose-oxygen deprivation, GGPP synthesis was decreased, leading to reduced prenylation of the small GTPase Rac1, increased binding of nonprenylated Rac1 to the scaffolding protein IQGAP1, and enhanced activation of the NLRP3 inflammasome. In response to restricted oxygen and glucose supply, patient monocytes with a compromised mevalonate pathway due to mevalonate kinase deficiency or Muckle-Wells syndrome released more IL-1β than did control monocytes. Thus, reduced GGPP synthesis due to inhibition of HMGCR under glucose-oxygen deprivation results in proinflammatory innate responses, which are normally kept in check by the prenylation of Rac1. We suggest that this mechanism is also active in inflammatory autoimmune conditions. Y1 - 2024 U6 - https://doi.org/10.1126/scisignal.add8913 SN - 1945-0877 VL - 17 IS - 845 PB - American Association for the Advancement of Science (AAAS) ER - TY - GEN A1 - Raps, Stefanie A1 - Bahr, Laura A1 - Karkossa, Isabel A1 - Rossol, Manuela A1 - Bergen, Martin von A1 - Schubert, Kristin T1 - Triclosan and its alternatives, especially chlorhexidine, modulate macrophage immune response with distinct modes of action T2 - Science of The Total Environment N2 - Since European regulators restricted the use of bacteriocidic triclosan (TCS), alternatives for TCS are emerging. Recently, TCS has been shown to reprogram immune metabolism, trigger the NLRP3 inflammasome, and subsequently the release of IL-1β in human macrophages, but data on substitutes is scarce. Hence, we aimed to examine the effects of TCS compared to its alternatives at the molecular level in human macrophages. LPS-stimulated THP-1 macrophages were exposed to TCS or its substitutes, including benzalkonium chloride, benzethonium chloride, chloroxylenol, chlorhexidine (CHX) and cetylpyridinium chloride, with the inhibitory concentration (IC10-value) of cell viability to decipher their mode of action. TCS induced the release of the pro-inflammatory cytokine TNF and high level of IL-1β, suggesting the activation of the NLRP3-inflammasome, which was confirmed by non-apparent IL-1β under the NLRP3-inhibitor MCC950 treatment d. While IL-6 release was reduced in all treatments, the alternative CHX completely abolished the release of all investigated cytokines. To unravel the underlying molecular mechanisms, we used untargeted LC-MS/MS-based proteomics. TCS and CHX showed the strongest cellular response at the protein and signalling pathway level, whereby pathways related to metabolism, translation, cellular stress and migration were mainly affected but to different proposed modes of action. TCS inhibited mitochondrial electron transfer and affected phagocytosis. In contrast, in CHX-treated cells, the translation was arrested due to stress conditions, resulting in the formation of stress granules. Mitochondrial (e.g. ATP5F1D, ATP5PB, UQCRQ) and ribosomal (e.g. RPL10, RPL35, RPS23) proteins were revealed as putative key drivers. Furthermore, we have demonstrated the formation of podosomes by CHX, potentially involved in ECM degradation. Our results exhibit modulation of the immune response in macrophages by TCS and its substitutes and illuminated underlying molecular effects. These results illustrate critical processes involved in the modulation of macrophages' immune response by TCS and its alternatives, providing information essential for hazard assessment. Y1 - 2024 U6 - https://doi.org/10.1016/j.scitotenv.2023.169650 SN - 0048-9697 VL - 914 PB - Elsevier BV ER -