Periodic Reporting for period 4 - MADEFUN (Regulation of Brain Macrophage Development and Function)
Periodo di rendicontazione: 2023-12-01 al 2025-05-31
Macrophages are part of the mononuclear phagocyte system and play essential roles in innate immunity. Beyond their immune functions, they perform critical organ-specific tasks that maintain tissue homeostasis. The central nervous system (CNS) harbors several macrophage populations, among which microglia represent the most abundant and well-characterized population residing within the parenchyma. Additional macrophage populations, collectively referred to as border-associated macrophages (BAMs), reside at the interface between the brain and the periphery, including the choroid plexus, perivascular spaces, and meninges. Most CNS macrophages originate during embryonic development; however, choroid plexus and dural macrophages are replenished by circulating monocytes in adulthood. Whether microglia and BAMs arise from a shared developmental program or distinct progenitor lineages remains unresolved. This project aimed to delineate the spatiotemporal emergence of BAMs and microglia, determine how the local microenvironment shapes their phenotype and function, and define their contributions to brain development, physiology, and disease. Our work will provided a comprehensive understanding of microglia and BAM biology and their functional specialization across 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 (Utz et al. Cell 2020).
The development of most macrophages depends on the colony-stimulating factor 1 (CSF-1) receptor, which has two ligands: CSF-1 and interleukin-34 (IL-34). While IL-34 is required for the homeostasis of microglia, it is unclear whether BAMs also depend on this cytokine. We demonstrated that the embryonic development of murine BAMs in the choroid plexus, leptomeninges, and perivascular spaces required CSF-1, while IL-34 was critical for their maintenance in adulthood. In the brain, Il34 was expressed by mural cells and perivascular fibroblasts, and its transgenic deletion in these cells interrupted BAM maintenance. Il34 deficiency coincided with transcriptional changes in vascular cells, leading to increased flow velocity and vasomotion in pial and penetrating arterioles. Similarly, Mrc1CreCsf1rfl/fl mice lacking CD206+ perivascular BAMs exhibited increased hemodynamics in arterial networks. These findings reveal a crosstalk between vascular cells and CNS macrophages regulating cerebrovascular function (Van Hove et al. Immunity 2025).
The development of most macrophages depends on the colony-stimulating factor 1 (CSF-1) receptor, which has two ligands: CSF-1 and interleukin-34 (IL-34). While IL-34 is required for the homeostasis of microglia, it is unclear whether BAMs also depend on this cytokine. We demonstrated that the embryonic development of murine BAMs in the choroid plexus, leptomeninges, and perivascular spaces required CSF-1, while IL-34 was critical for their maintenance in adulthood. In the brain, Il34 was expressed by mural cells and perivascular fibroblasts, and its transgenic deletion in these cells interrupted BAM maintenance. Il34 deficiency coincided with transcriptional changes in vascular cells, leading to increased flow velocity and vasomotion in pial and penetrating arterioles. Similarly, Mrc1CreCsf1rfl/fl mice lacking CD206+ perivascular BAMs exhibited increased hemodynamics in arterial networks. These findings reveal a crosstalk between vascular cells and CNS macrophages regulating cerebrovascular function (Van Hove et al. Immunity 2025).
The research project provided a better understanding of the development and biology of microglia and BAMs, their cytokine requirements and distinct functional specializations at various stages of life.