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Regulation of Brain Macrophage Development and Function

Periodic Reporting for period 2 - MADEFUN (Regulation of Brain Macrophage Development and Function)

Reporting period: 2020-12-01 to 2022-05-31

Macrophages are part of the mononuclear phagocyte system and play critical roles in innate immune responses. They further exert crucial organ-specific functions to warrant tissue homeostasis. The central nervous system (CNS) contains several macrophage populations, of which microglia are the most prominent and abundant population residing in the CNS parenchyma. At the interface between the brain and the periphery reside choroid plexus, perivascular and meningeal macrophages (‘border-associated’ macrophages, BAMs).
Most CNS macrophages emerge during development, with the exception of choroid plexus and dural macrophages, which are replaced by monocytes in adulthood. Whether microglia and BAMs share a common developmental program or arise from separate lineages remains unknown. Our goal is to delineate the spatiotemporal emergence of BAMs and microglia, to analyze the impact of the local microenvironment on their phenotype and function and to investigate their role in brain development and their specific functions in physiological and neuropathological conditions. This project will provide a deeper insight into microglia and BAM biology and their functional specializations at different stages of life.
We identified two phenotypically, transcriptionally and locally distinct brain macrophages throughout development, giving rise to either microglia or BAMs. We found that two macrophage populations were already present in the yolk sac suggesting an early segregation. Using fate-mapping models, we showed that similar to microglia, BAMs mostly derived from early erythro-myeloid progenitors in the yolk sac. The development of microglia was dependent on the cytokine TGF-β whereas the genesis and maturation of BAMs occurred independently of this cytokine. Collectively, our data show that developing parenchymal and non-parenchymal brain macrophages are separate entities in terms of ontogeny, gene signature and requirement for TGF-β.
Until the end of the project, we aim to investigate the role of the different brain macrophages in pathological conditions, such as neuroinflammatory and neurodegenerative disorders.
Graphical Abstract