26rhk040 10.3205/26rhk040 urn:nbn:de:0183-26rhk0402 Meeting Abstract Mittrowann Mittrowann Ricarda R

Institut für Immunologie, Universität Münster, Münster, Deutschland

author Bieß Bieß Nadine N

Institute für Lebensmittelchemie, Universität Münster, Münster, Deutschland

author Gerdemann Gerdemann Andrea A

Institute für Lebensmittelchemie, Universität Münster, Münster, Deutschland

author Behrens Behrens Matthias M

Institute für Lebensmittelchemie, Universität Münster, Münster, Deutschland

author Humpf Humpf Hans-Ulrich HU

Institute für Lebensmittelchemie, Universität Münster, Münster, Deutschland

author Hasseli-Fräbel Hasseli-Fräbel Rebecca R

Abteilung für Rheumatologie und klinischer Immunologie, Universitätsklinikum Münster, Münster, Deutschland

author Austermann Austermann Judith J

Abteilung für Anästhesiologie, operative Intensivmedizin und Schmerztherapie, Universitätsklinikum Münster, Münster, Deutschland Institut für Immunologie, Universität Münster, Münster, Deutschland

author Roth Roth Johannes J

Institut für Immunologie, Universität Münster, Münster, Deutschland

author German Medical Science GMS Publishing House

Düsseldorf

610 20260909 engl This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). M0656 040 Deutsche Gesellschaft für Rheumatologie Deutsche Gesellschaft für Orthopädische Rheumatologie Gesellschaft für Kinder- und Jugendrheumatologie 54. Kongress der Deutschen Gesellschaft für Rheumatologie und Klinische Immunologie (DGRh), 36. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR), 40. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh) Deutscher Rheumatologiekongress 2026 Experimentelle & Translationale Rheumatologie Leipzig 20260909 20260912 ET.14 TextIntroduction: Vaccinating patients with immune-mediated inflammatory diseases (IMIDs) poses two key challenges: Impaired vaccine responses due to immunosuppression and the risk of disease flares triggered by adjuvant-induced innate immune activation. Many adjuvants act via pattern recognition receptors (PRRs), including Toll-like receptor 4 (TLR4). In rheumatoid arthritis (RA), endogenous ligands such as S100A8/A9 chronically activate TLR4, leading to persistent monocyte/macrophage (Mφ) priming. Thus, innate immune cells in RA operate in a pre-activated state, which may alter their response to vaccines. Emerging evidence suggests that metabolic reprogramming critically shapes Mφ inflammatory responses.The aim of this study is to elucidate the metabolic and functional mechanisms underlying sustained TLR4-induced macrophage reprogramming and to determine how this altered state shapes responses to vaccines with distinct adjuvant profiles.Methods: HoxB8-derived Mφ were exposed to prolonged TLR4 stimulation to model chronic PRR activation. Metabolic profiling was performed tandem mass spectrometry (HILIC-MS/MS). Immune responses upon TLR4 restimulation were assessed by TNFα ELISA and qPCR. Mitochondrial function was analyzed using flow cytometry. Metabolic pathways were targeted using inhibitors of pyruvate dehydrogenase kinase 1 (PDHK1) and glutaminase 1 (GLS1). Nuclear factor erythroid 2-related factor 2 (Nrf2) activity was assessed by Western blot and inhibited using ML385. Three licensed respiratory syncytial virus (RSV) vaccines with distinct adjuvant mechanisms were tested under basal and pre-activated conditions.Results: Sustained TLR4 activation induced stable metabolic and functional reprogramming of Mφ, characterized by Krebs cycle disruption, reduced ATP production, mitochondrial dysfunction, and altered urea cycle metabolism. Nrf2 emerged as a central regulator, with glutamine metabolism being essential for establishing this state. Pharmacological inhibition of PDHK1 and GLS1 reversed key metabolic alterations. In translational experiments, RSV vaccines induced distinct activation profiles depending on their adjuvant composition, leading to differential responses upon subsequent inflammatory stimulation.Conclusion: Chronic TLR4 stimulation reprograms Mφ metabolism and function, altering responses to subsequent PRR activation. These findings indicate that vaccine-induced immune responses may differ in RA due to innate immune pre-activation, underscoring the need to consider disease-specific immune states in vaccine design. Pruenster M Vogl T Roth J Sperandio M S100A8/A9: From basic science to clinical application 2016 Pharmacol Ther 120-131 Pruenster M, Vogl T, Roth J, Sperandio M. S100A8/A9: From basic science to clinical application. Pharmacol Ther. 2016 Nov;167:120-131. DOI: 10.1016/j.pharmthera.2016.07.015 http://dx.doi.org/10.1016/j.pharmthera.2016.07.015 Pulendran B S Arunachalam P O'Hagan DT Emerging concepts in the science of vaccine adjuvants 2021 Nat Rev Drug Discov 454-475 Pulendran B, S Arunachalam P, O'Hagan DT. Emerging concepts in the science of vaccine adjuvants. Nat Rev Drug Discov. 2021 Jun;20(6):454-475. DOI: 10.1038/s41573-021-00163-y http://dx.doi.org/10.1038/s41573-021-00163-y 0 0 0 0