Differential Role of Metabolic Signaling Molecules on Articular Effector Cells in Inflammatory Joint Diseases

• Applicant: Dr. Klaus Frommer
• Subject Area: Rheumatology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407115149

The term immunometabolism describes the finding that a link exists between immunological processes and cellular metabolism. In this respect it has been shown that hormone- and/or cytokine-like molecules as well as metabolites can act as signaling molecules influencing inflammation, destruction and proliferation. These processes are also essential determinants in the pathophysiology of inflammatory rheumatic diseases.Based on our working hypothesis that these signaling molecules have differential pathophysiologically relevant effects on articular effector cells, which are based on different or variably pronounced mechanisms of action, and that there are interactions regarding the effects of these signaling molecules, we are going to investigate in this project which mechanisms are essential factors in the differential effects of metabolic signaling molecules on articular effector cells. By this, we would like to identify potential targets of their influence on chronic inflammatory joint diseases. The following questions are going to be addressed:1) Which differential effects do free fatty acids (FFA) have on the intracellular energy metabolism of synovial fibroblasts (e.g. ATP production) as a potential energy source for the production of proinflammatory and destructive effector molecules? Do the changes in ATP production correlate with the secreted amounts of IL-6?2) Is the intracellular synthesis of lipids increased by chronic exposure to FFA?3) Which effect do lactate and succinate have on synovial fibroblasts (SF) regarding the expression and secretion of proinflammatory and matrix degrading factors?4) Is the ROS production of SF affected by succinate?5) Are there differential effects of lactate and succinate on SF from patients with different disease backgrounds (RA, OA, PsA)?6) How does the signaling of palmitic acid, stearic acid and oleic acid differ in chondrocytes and endothelial cells? Can this explain the differences observed between the various FFA?7) How do the signaling molecules of the metabolism act in combination? Are there any interactions (synergistic/antagonistic effects)?8) Does the co-culture of synovial fibroblasts with adipocytes have a similar effect as the direct addition of free fatty acids? Can this effect be diminished by inhibition of fatty acid de novo synthesis, by inhibition of lipolysis or by blocking the fatty acid binding protein 4?9) Can the adipokine/fatty acid/metabolite-induced proinflammatory and destructive processes be reduced by intracellular inhibitors/medications? Are there differences between the distinct rheumatic diseases and can the differential clinical responses be explained by this?

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Ulf Müller-Ladner; Privatdozentin Dr. Elena Neumann