Summary of the research programme
Myeloid cells in the central nervous system (CNS) represent a heterogeneous class of innate immune cells that differentially contribute to the maintenance of tissue homeostasis during development, adulthood and disease. In recent years, we have witnessed an explosion of research into understanding the role of myeloid cells in the brain, and the CRC/TRR167 NeuroMac has been at the forefront of these activities. The novel studies used cell-specific targeting, in vivo imaging, single-cell expression analysis and other sophisticated tools to increase our knowledge about the CNS immune cell compartment. The results have fundamentally changed our views on the origin, fate and function of distinct myeloid subsets in the CNS.
Furthermore, new concepts of CNS macrophage biology that are emerging from these new results have broad implications for our understanding and treatment of CNS diseases. For example, many genetic alterations that are associated with increased risk for neurological and psychiatric disorders, including schizophrenia, autism spectrum disorder, multiple sclerosis (MS), and Alzheimer’s disease (AD), affect genes that are highly expressed by CNS myeloid cells such microglia. As a result, myeloid cells have emerged as a possible therapeutic target for CNS disorders. However, the complex mechanisms that underlie the contributions of myeloid cells in health and disease are not well defined yet. Therefore, the NeuroMac collaborative research consortium aims to further define – at molecular, cellular and organismic level – how myeloid cell impairments contribute to CNS dysfunction.
In the first funding period, we have made substantial research efforts to elucidate the role of myeloid cells including microglia during brain diseases with a special focus on myeloid cell heterogeneity. Members of the CRC/TRR167 NeuroMac consortium introduced novel single-cell technologies in the field of neuroimmunology such as single-cell RNA-sequencing (RNA-Seq), single-cell sequencing assay for transposase-accessible chromatin-sequencing (scATAC-seq), single-cell mass spectrometry (cytometry by time-of-flight [CyTOF]), which allowed us to characterize for the first time human microglia and discover targetable disease-linked microglia states. In detail, the consortium was able to identify novel context-associated microglia states during ontogeny, homeostasis and disease conditions, such as multiple sclerosis (MS), brain tumors and Alzheimer’s disease (AD). Interspecies differences of microglia marker profiles were identified permitting new insights into the role of myeloid cells in human CNS disorders. Newly established multicolor fate mapping and Ribotag approaches further allowed to monitor myeloid cells kinetics in distinct disease stages and their underlying transcriptional signatures. Overall, the first funding period of the CRC/TRR167 NeuroMac consortium was very successful, resulting in several milestone discoveries in neuroimmunology.
In the second funding period, we would like to draw on the resources of the first funding period. In detail, we plan to determine the molecular mechanisms that govern myeloid cell identity, and focus on the interactions of CNS myeloid cells with neurons and macroglia, which are essential to establish context-associated microglia states. The newly identified microglia clusters will now be spatially mapped in brain pathologies using cutting-edge spatial genomic and proteomic tools. We shall also use newly developed transgenic mouse models for fate mapping and gene targeting to interfere with myeloid cells functions. Seven new projects have been carefully selected to strengthen these innovative topics. The CRC/TRR167 NeuroMac consortium plans to address a variety of neurological, psychiatric and immunological disorders, including stroke, MS, encephalitis, meningitis, AD, Huntington’s disease (HD), CNS lupus and immunotherapy-induced disease, to get new insights into the role of brain myeloid cells in CNS disorders, which may open new therapeutic avenues.
The long-term goal of the NeuroMac consortium is to facilitate the transfer of knowledge obtained from basic research on brain myeloid cells to the improvement of patient care by providing sufficient preclinical evidence for later ‘bench-to-bedside’ translation and by deciphering the fundamental mechanisms of myeloid cell biology in the CNS during health and disease. In order to achieve this ambitious long-term goal, we need to provide more 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 main goal of the second funding period is to better understand the molecular mechanisms of myeloid cell diversity in the CNS and the interactions of microglia with neurons and other glial cells during development, health and perturbation.
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