Driven by recent technological breakthroughs, “immunometabolism” has become an exciting area of biomedical research. Recent observations indicate that the metabolic interface of macrophages can be a major determinant of an immune response. They are present within all tissues in the body, contributing to homeostasis, immune defense, and repair. Whereas a close association of distinct metabolic states with activation levels of macrophages has been described in vitro, the immunometabolic relevance of macrophages in tissues is more complex. In tissues, resident and infiltrating macrophages respond with specific adaptations, which are amongst others reflected in their metabolism. While descriptive accounts of specific alterations in macrophages are accumulating, the biological significance of the metabolic interaction with tissues, the contribution to the immunoregulatory framework, and the relevance for cell function remains largely obscure. Elucidating the metabolic crosstalk of macrophages with tissue and learning how to manipulate the interactions to explore their functional relevance might serve as a paradigm for other cells of the immune system.
We pursue three basic research objectives:
1) Exploration of the immunometabolic profile of macrophage populations in vivo
2) Characterization of the metabolic crosstalk of macrophages with tissues in health and disease
3) Identification of immunometabolic targets in human disease.
We aim to systematically characterize the metabolic setup of different macrophage populations in vivo to elucidate tissue-specific adaptions. Moreover, we will explore the metabolic cues and tissue-specific crosstalk between macrophages with tissue environments in detail. We have initially chosen the intestine and its microbiota as well as adipose tissue because macrophages are crucial to maintain tissue integrity of those. This focus enables a careful connection of the individual sub-projects by a consortium with strong expertise in relevant mouse models, organoids, and access to human samples.
The research field “Immunometabolism” studies intracellular metabolic pathways in immune cells that affect their function. Principally, cells flexibly utilize the available energy substrates using different metabolic pathways. Recent findings highlight that the use of distinct metabolic pathways directly regulates immune cell function. For example, immune cells that are acutely activated during a bacterial infection in order to kill the pathogen, rely on fermentation as a metabolic pathway to break down sugar. In contrast, cells responsible for tissue repair after the infection is cleared, prefer respiration to break down sugar. To date it is not understood why immune cells switch metabolism and how this switch alters their function. Current knowledge of immune metabolism is based primarily on in vitro experiments. However, the metabolic environment in the cell culture dish differs largely from the conditions in our body and is also different in the individual organs. The concentration of glucose, for example, is 10 times lower in the lungs than in the blood, while fatty acid concentrations are greatly increased in the intestine and adipose tissue. According to the motto "You are what you eat," it is believed that the availability of nutrients in the tissues directly controls immune functions. Furthermore, it is assumed that a malfunction in these metabolic processes, underlies many diseases. Pharmacological intervention in the aberrant metabolic processes of immune cells offers new therapeutic approaches to treat chronic diseases. How these different metabolites influence immune function, and how they ensure the integrity of the respective organ, is completely unclear. Our consortium aims to answer these questions together. Macrophages represent the ideal immune cells to study the role of immune metabolism in tissues. Macrophages are evolutionary ancient cells already present in the most primitive multicellular organisms. They play an essential role in maintaining tissue integrity by phagocytosing ("eating") old or diseased tissue cells or pathogenic microorganisms and viruses. Consequently, macrophages have learned to adapt to a wide variety of ingested metabolites, the metabolization of which in turn affects their immune function. The multidisciplinary team consisting of experts in metabolism, immunology, biochemistry, epigenetics, biophysics, and the microbiome will study the metabolic functions of macrophages specifically in the gut and adipose tissue. Animal models, patients and innovative organoid cultures will be used to study human diseases in these tissues in order to find new therapeutic targets for inflammatory bowel disease, cancer, obesity, or diabetes.
Prof. Katrin ANDREASSON
Stanford University, USA
Katrin is Professor in the Department of Neurology and Neurological Sciences, at Stanford University. The objectives of her laboratory research are to identify specific inflammatory and metabolic pathways that may be targeted to prevent and treat neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease.
Prof. Peter MURRAY
Max Planck Institute, Germany
Peter is group leader and Professor at the Max Planck Institute of Biochemistry in Martinsried. He investigates various aspects of macrophage biology and focuses how immune cells sense and transfer information about metabolites including amino acids into growth and activation decisions.
Prof. Christian WOLFRUM
ETH Zürich, Switzerland
Christian is Professor of the Institute of Food Nutrition and Health at the ETH Zurich. He uses a translational approach to understand the molecular mechanisms regulating brown and white adipocyte formation and activity with a focus on obesity-associated metabolic complications.