Summary of the research programme
In recent years, we have witnessed an explosion of research into understanding the role of myeloid cells in the developing, healthy, aging and diseased brain. Seminal work showed that microglia, central nervous system (CNS)-associated macrophages, dendritic cells and monocyte-derived cells are critical effectors and sculptors of changes in their environment and are able to respond to them. Furthermore, sessile myeloid cells in the CNS unexpectedly have major roles in the maintenance of the tissue and critically shape neuronal wiring during development. Disturbances of these processes are suggested to play a central role in the development of many neurological and psychiatric disorders. However, the complex mechanisms that underlie the contributions of myeloid cells in health and disease are not well defined yet.
For example, it was assumed for a long time that all tissue macrophages originate from populations of bone marrow-derived myeloid cells that circulate in the blood as monocytes and seed organs as macrophages in the steady state and during inflammation. This simplified view has changed dramatically due to the recent discovery of new subtypes of mononuclear phagocytes and their distinct and non-redundant roles in CNS disorders. In fact, it has become clear that microglia and myeloid cells, such as monocytes, macrophages, and dendritic cells are ontogenetically and also functionally distinct innate immune cell populations in the brain.
Substantial research efforts have been made over the last decades to elucidate the role of myeloid cells including microglia during brain diseases, but these attempts were hampered by technical limitations. Due to the recent availability of new techniques in cell imaging, gene targeting and molecular biology, the research on myeloid cells has gained momentum in both neuroscience and immunology. The DFG-funded Research Unit (FOR) 1336 (coordinators: Marco Prinz & Josef Priller), which was established in 2010, represented one initial approach effort to study the conditions that influence the fate of myeloid cells in the CNS with the establishment and use of these new tools. Overall, the Research Unit FOR1336 was very successful and gained worldwide recognition, resulting in several mile-stone discoveries in neuroimmunology. The FOR1336 paved the way for future investigations in both basic and disease-oriented research for years to come.
In this Collaborative Research Centre/Transregio (CRC/TRR) initiative, we would like to draw on the resources of the FOR1336, and extend the investigations to new fields with the aim of elucidating the functions of myeloid cells in the nervous system during development, health and disease (NeuroMac). A special focus will be on parenchymal macrophages (microglia), non-parenchymal CNS macrophages, circulating monocytes and bone marrow myeloid cells (e.g. myeloid progenitors). Ultimately, we strive to translate the findings made in animal models to the human condition. The NeuroMac initiative will therefore address a variety of neurological, psychiatric and immunological disorders, including stroke, multiple sclerosis (MS), meningitis, Alzheimer’s disease (AD), Huntington’s disease (HD), obesity and graft-versus-host disease. We aim to provide sufficient preclinical evidence for later ‘bench-to-bedside’ translation.
New insights into the universe of brain myeloid cells are likely to have significant clinical implications for the treatment of severe brain diseases such as AD, stroke, multiple sclerosis, but also psychiatric disorders such as schizophrenia, autism, and many others. In theory, if the practical hurdles can be overcome, specific myeloid populations such as phagocytes from the yolk sac, bone marrow or blood, might be used to exert neuroprotective functions or deliver therapeutic molecules into the CNS. In the NeuroMac initiative, we therefore aim to significantly extend our understanding of the origin, fate and function of microglia compared to other macrophage populations. This will help to design new strategies to promote restoration of tissue homeostasis in the CNS.
The long-term goal of the NeuroMac initiative is to facilitate the transfer of knowledge obtained from basic research on brain myeloid cells to the improvement of patient care. To achieve this ambitious long-term goal, we first need to provide the scientific basis by deciphering the fundamental mechanisms of myeloid cell biology in the CNS during health and disease.
Detailed presentation of the research programme
The goal of the NeuroMac initiative is to obtain insights into the diverse functions of myeloid cells in the CNS during development, health and disease. A particular focus will be on parenchymal macrophages (microglia), circulating monocytes and bone marrow myeloid cells (e.g. myeloid progenitors). Combining studies of brain myeloid cell development and homeostasis, neurobiology, cell migration and neuropathology in one research initiative will enable a fruitful and productive interactions between the groups involved.
To this end, this CRC/TRR initiative aims to:
- define common and distinct genetic pathways for the development of different sets of myeloid cells in the brain
- identify the cellular mechanisms of myeloid cell function during the onset, resolution and recovery of disease in models of neurodegeneration and neuroinflammation
- investigate the therapeutic potential of myeloid cells in preclinical models of CNS diseases