Elucidating the function of antioxidants and ROS on metabolism and inflammation in macrophages and B cells

• Applicant: Professor Dr. Karsten Hiller
• Subject Area: Immunology ; Biochemistry
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413710817

Immune-mediated diseases such as autoimmunity and infections are driven by a deregulated immune system that involves regulatory mechanisms in lymphocytes, but also innate immune cells like macrophages. In multiple sclerosis, an autoimmune disease that affects the central nervous system, immunopathology evident by axon demyelination and neurodegeneration that has severe consequences for the affected patients and is the most frequent cause of non-reversible disabilities in young adults. However, treatment options are limited and either lack effectiveness or have tremendous side effects. An attractive approach might be the interference with metabolic cascades that are implicated in immune cell functionality. Increased levels of reactive oxygen species (ROS) are found in metabolic active cells and in inflammatory diseases. There is evidence that ROS regulate macrophage/microglia pro-inflammatory/anti-inflammatory capacities, which are cellular key drivers of neuroinflammation. Increased ROS in human multiple sclerosis are a typical observed pathological feature. This indicates a disturbed cellular redox state in the disease context and that redox regulation is crucial for the maintenance of normal cellular functions and cellular homeostasis. Our previous work has identified that controlling ROS by the antioxidant glutathione (GSH) is fundamental for the metabolic control of inflammatory T cells and thus has opened up a new perspective to cope with disordered cells in vivo. However, whether this is a unified function of GSH is currently unknown, especially as different immune cell types have different metabolic requirements. Our aim is to discover novel subset-specific pathways and targets that may offer new therapeutic options for inflammatory diseases and/or neurodegenerative disorders such as MS. Therefore we will will interfere with ROS-scavenging by the use of genetic approaches in mice to target redox homeostasis in combination with in vivo disease models that are relevant for human autoimmune diseases and infections. We will focus on inflammatory cells in the innate immune system, mainly macrophages and B cells, which are crucial for adaptive immunity. We will metabolically profile both macrophages and B cells in the specific disease context and will align these changes to the observed phenotypes. We will identify, characterize and manipulate cell specific intrinsic metabolic and signaling pathways that are associated with a protective or detrimental immune response. Thus, identification of cell or disease specific metabolic signatures or pathway specificities will be an important step for the further development of immune-metabolism targeted therapeutic strategies.

• DFG Programme: Research Grants
• International Connection: Luxembourg
• Cooperation Partner: Professor Dr. Dirk Brenner