Metabolic-secretory decoupling defines a disease-intrinsic state in rheumatoid arthritis monocytes

Teoh, S. T.; Malkewitz, S.; Iperi, C.; Makowiec, C.; Kakale, A.; Duphey, S. M.; Boersch, A.; Buczak, K.; Wolski, W.; Yang, M.; Frezza, C.; Ospelt, C.; Distler, O.; Kyburz, D.; Mueller-Durovic, B.

doi:10.64898/2026.04.23.720351

bioRxiv · 10.64898/2026.04.23.720351

Metabolic-secretory decoupling defines a disease-intrinsic state in rheumatoid arthritis monocytes

Teoh, S. T.·Malkewitz, S.·Iperi, C.·Makowiec, C.·Kakale, A.·Duphey, S. M.·Boersch, A.·Buczak, K.·Wolski, W.·Yang, M.·Frezza, C.·Ospelt, C.·Distler, O.·Kyburz, D.·Mueller-Durovic, B.

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Abstract

ObjectivesCirculating monocytes from rheumatoid arthritis (RA) patients are pre-primed for inflammatory activation, but their disease-intrinsic features have not been systematically characterized. Given the important role of metabolism in shaping immune cell function, we aimed to determine how this pre-primed state is underpinned metabolically and whether these changes persist across different activation states, using an unbiased multi-omics approach. MethodsPeripheral blood CD14 monocytes from RA patients and matched healthy donors were analyzed in an undifferentiated state (M0) and after differentiation into classically activated M(IFN{gamma}+LPS) and alternatively activated M(IL-4) macrophages, followed by acute lipopolysaccharide (LPS) stimulation. Metabolomic (untargeted LC-MS/MS), transcriptomic (RNA-seq), and proteomic (label-free mass LC-MS/MS) profiling were performed. Data was comprehensively analyzed by weighted gene correlation network analysis, differential analysis, gene set enrichment analysis, multi-omics factor analysis and metabolic flux modeling. ResultsRA monocytes exhibited a stable disease-driven signature across activation states. Integration of metabolomic, transcriptomic and proteomic data revealed an unexpected convergence on metabolic-secretory coupling, with depletion of nucleotide and redox metabolites, downregulation of mitochondrial and translational pathways, and remodeling of the secretory apparatus, including loss of cis-Golgi components. Consistently, metabolic modeling predicted reduced glycosylation fluxes, connecting metabolic changes to altered secretory capacity. ConclusionsRA monocytes adopt a stable, disease-intrinsic state that persists across activation conditions. Multi-omics data identify a linked metabolic and secretory defect, with reduced glycosylation capacity as a potential functional consequence. This metabolic-secretory coupling represents a defining feature of RA monocyte dysfunction and a potential therapeutic target.

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Teoh, S. T., Malkewitz, S., Iperi, C., Makowiec, C., Kakale, A., Duphey, S. M., Boersch, A., Buczak, K., Wolski, W., Yang, M., Frezza, C., Ospelt, C., Distler, O., Kyburz, D., Mueller-Durovic, B.. 2026-04-27. Metabolic-secretory decoupling defines a disease-intrinsic state in rheumatoid arthritis monocytes. https://doi.org/10.64898/2026.04.23.720351

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